{"entity": "researcher", "timestamp": "2026-08-20T20:41:16.885Z", "family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "affiliations": ["Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47"}}, "publications": [{"entity": "publication", "iuid": "172755f770e243579d9d401b29efec67", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/172755f770e243579d9d401b29efec67.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/172755f770e243579d9d401b29efec67"}}, "title": "Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1.", "authors": [{"family": "Varga", "given": "Marek", "initials": "M", "orcid": "0000-0002-9685-8145", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/707532fc225c49d1b2d4f9bec632e13f.json"}}, {"family": "Ortis", "given": "Florian", "initials": "F"}, {"family": "Del Prado", "given": "Alicia", "initials": "A", "orcid": "0000-0002-5480-0367", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7625321e94ab4cb5ba256de247cd0fcd.json"}}, {"family": "Eddershaw", "given": "Alice", "initials": "A", "orcid": "0000-0002-8381-4135", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bef07e3914ad492d99119e687845f3c4.json"}}, {"family": "Scaletti Hutchinson", "given": "Emma", "initials": "E", "orcid": "0000-0002-8741-8981", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/77be7f5d51564a75a753579e976c7c72.json"}}, {"family": "Hank", "given": "Emily C", "initials": "EC", "orcid": "0000-0002-3777-4697", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2b412977f2364bef9ec63aa5e552331a.json"}}, {"family": "Zhou", "given": "Kaixin", "initials": "K"}, {"family": "Rudolfov\u00e1", "given": "Nat\u00e1lie", "initials": "N"}, {"family": "Dodaro", "given": "Alessia", "initials": "A"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Karsten", "given": "Stella", "initials": "S"}, {"family": "Mamonov", "given": "Kirill", "initials": "K"}, {"family": "Ahmed", "given": "Sara H", "initials": "SH"}, {"family": "Bentley", "given": "Kirsty", "initials": "K"}, {"family": "Wallner", "given": "Olov", "initials": "O"}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Prejan\u00f2", "given": "Mario", "initials": "M", "orcid": "0000-0002-9140-6246", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3149d1c394e5447b873012134ed902ac.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}, {"family": "de Vega", "given": "Miguel", "initials": "M", "orcid": "0000-0003-1285-7549", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6196fa790b4645c3acef45a87cdac3d0.json"}}, {"family": "Watson", "given": "Allan J B", "initials": "AJB", "orcid": "0000-0002-1582-4286", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/991264ae319e4e95a51e0b47b995c66e.json"}}, {"family": "Michel", "given": "Maurice", "initials": "M"}], "type": "journal article", "published": "2025-11-13", "journal": {"title": "J Med Chem", "issn": "1520-4804", "volume": "68", "issue": "21", "pages": "22455-22483", "issn-l": "0022-2623"}, "abstract": "The base excision repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1) plays a central role in maintaining genome integrity and mediating cellular responses to oxidative stress. As such, it represents an attractive target for pharmaceutical modulation. Small-molecule organocatalytic switches (ORCAs) greatly enhance the rate of OGG1-catalyzed cleavage of DNA abasic sites, thereby accelerating DNA repair. Here, we present the discovery and hit-to-lead optimization of a novel class of highly potent serotonin-derived ORCAs with greatly improved pharmacokinetic properties. Biochemical assays, X-ray crystallography, and molecular dynamics simulations point toward a water-mediated mechanism of activation, distinct from previously proposed Br\u00f8nsted base-assisted models. These findings establish serotonin-based ORCAs as promising chemical probes and potential leads for therapeutic modulation of OGG1 in oxidative stress-driven diseases.", "doi": "10.1021/acs.jmedchem.5c01454", "pmid": "41092057", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12621200"}], "notes": [], "created": "2026-08-20T08:10:54.321Z", "modified": "2026-08-20T08:10:54.746Z"}, {"entity": "publication", "iuid": "140cd67bdbfe479ab8cbcd20eaeca0ea", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/140cd67bdbfe479ab8cbcd20eaeca0ea.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/140cd67bdbfe479ab8cbcd20eaeca0ea"}}, "title": "The anabolic steroid stanozolol is a potent inhibitor of human MutT homolog 1.", "authors": [{"family": "Scaletti Hutchinson", "given": "Emma", "initials": "E"}, {"family": "Gustafsson Westergren", "given": "Robert", "initials": "R"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS"}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}], "type": "journal article", "published": "2025-10-00", "journal": {"title": "FEBS Lett.", "issn": "1873-3468", "volume": "599", "issue": "19", "pages": "2790-2801", "issn-l": "0014-5793"}, "abstract": "Human MutT homolog 1 (hMTH1) removes damaged nucleotides from the nucleotide pool, preventing their incorporation into DNA. Due to its potential as an anticancer drug target, hMTH1 has been the focus of several inhibitor development studies. Unexpectedly, we show that the anabolic steroid stanozolol (Stz) is a potent nanomolar inhibitor of hMTH1. We present the structure of hMTH1 in complex with Stz, which indicates a unique core scaffold that could be exploited for future inhibitor development. Comparison with human protein structures bound with dihydrotestosterone (DHT) shows hMTH1 is entirely unrelated in terms of its structure. As these DHT binding proteins are all involved in steroid regulation, this makes the identification of Stz as a potent hMTH1 inhibitor all the more unusual.", "doi": "10.1002/1873-3468.70116", "pmid": "40878820", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12519060"}], "notes": [], "created": "2026-08-20T06:25:27.525Z", "modified": "2026-08-20T06:25:27.657Z"}, {"entity": "publication", "iuid": "c779c1cba84c4c2595cf59774de80e18", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/c779c1cba84c4c2595cf59774de80e18.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/c779c1cba84c4c2595cf59774de80e18"}}, "title": "Blind De Novo Design of Dual Cyclic Peptide Agonists Targeting GCGR and GLP1R", "authors": [{"family": "Li", "given": "Qiuzhen", "initials": "Q", "orcid": "0009-0009-2913-4786", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f3d7b87dcea3440d8eaa4b574a88da3e.json"}}, {"family": "Wiita", "given": "Elisee", "initials": "E"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Bryant", "given": "Patrick", "initials": "P", "orcid": "0000-0003-3439-1866", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6a683bcf98234ff09b2398976583b66f.json"}}], "type": "posted-content", "published": "2025-06-08", "journal": {"issn-l": null}, "abstract": null, "doi": "10.1101/2025.06.06.658268", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T11:06:04.818Z", "modified": "2026-08-20T11:06:04.891Z"}, {"entity": "publication", "iuid": "b28fc4cc0e8a4eaca57d651057592f0b", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/b28fc4cc0e8a4eaca57d651057592f0b.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/b28fc4cc0e8a4eaca57d651057592f0b"}}, "title": "Kinetic and structural characterization of NUDT15 and NUDT18 as catalysts of isoprene pyrophosphate hydrolysis.", "authors": [{"family": "Scaletti", "given": "Emma R", "initials": "ER"}, {"family": "Unterlass", "given": "Judith E", "initials": "JE"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Vallin", "given": "Karl S", "initials": "KS"}, {"family": "Kapsitidou", "given": "Despina", "initials": "D"}, {"family": "Tsuber", "given": "Viktoriia", "initials": "V"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/51f26d370fb74994b8e2b4fa1c9c2f7a.json"}}], "type": "journal article", "published": "2024-10-00", "journal": {"title": "FEBS J.", "issn": "1742-4658", "volume": "291", "issue": "19", "pages": "4301-4322", "issn-l": "1742-464X"}, "abstract": "Isoprene pyrophosphates play a crucial role in the synthesis of a diverse array of essential nonsterol and sterol biomolecules and serve as substrates for posttranslational isoprenylation of proteins, enabling specific anchoring to cellular membranes. Hydrolysis of isoprene pyrophosphates would be a means to modulate their levels, downstream products, and protein isoprenylation. While NUDIX hydrolases from plants have been described to catalyze the hydrolysis of isoprene pyrophosphates, homologous enzymes with this function in animals have not yet been reported. In this study, we screened an extensive panel of human NUDIX hydrolases for activity in hydrolyzing isoprene pyrophosphates. We found that human nucleotide triphosphate diphosphatase NUDT15 and 8-oxo-dGDP phosphatase NUDT18 efficiently catalyze the hydrolysis of several physiologically relevant isoprene pyrophosphates. Notably, we demonstrate that geranyl pyrophosphate is an excellent substrate for NUDT18, with a catalytic efficiency of 2.1 \u00d7 105 m-1\u00b7s-1, thus making it the best substrate identified for NUDT18 to date. Similarly, geranyl pyrophosphate proved to be the best isoprene pyrophosphate substrate for NUDT15, with a catalytic efficiency of 4.0 \u00d7 104 M-1\u00b7s-1. LC-MS analysis of NUDT15 and NUDT18 catalyzed isoprene pyrophosphate hydrolysis revealed the generation of the corresponding monophosphates and inorganic phosphate. Furthermore, we solved the crystal structure of NUDT15 in complex with the hydrolysis product geranyl phosphate at a resolution of 1.70 \u00c5. This structure revealed that the active site nicely accommodates the hydrophobic isoprenoid moiety and helped identify key binding residues. Our findings imply that isoprene pyrophosphates are endogenous substrates of NUDT15 and NUDT18, suggesting they are involved in animal isoprene pyrophosphate metabolism.", "doi": "10.1111/febs.17202", "pmid": "38944687", "labels": [], "xrefs": [{"db": "RefSeq", "key": "XP_003984764.1"}], "notes": [], "created": "2026-08-20T11:18:05.835Z", "modified": "2026-08-20T11:18:05.916Z"}, {"entity": "publication", "iuid": "05055972eaff415c8f51b09d91d400fd", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/05055972eaff415c8f51b09d91d400fd.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/05055972eaff415c8f51b09d91d400fd"}}, "title": "The one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation.", "authors": [{"family": "Marttila", "given": "Petra", "initials": "P", "orcid": "0000-0002-0115-8067", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4ed95784f80a45d9abb072fbb74fc225.json"}}, {"family": "Bonagas", "given": "Nadilly", "initials": "N"}, {"family": "Chalkiadaki", "given": "Christina", "initials": "C"}, {"family": "Stigsdotter", "given": "Hannah", "initials": "H"}, {"family": "Schelzig", "given": "Korbinian", "initials": "K", "orcid": "0009-0001-3791-0716", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a5ffa105eeea4750a28fd7b1f4b3e4de.json"}}, {"family": "Shen", "given": "Jianyu", "initials": "J"}, {"family": "Farhat", "given": "Crystal M", "initials": "CM"}, {"family": "Hondema", "given": "Amber", "initials": "A"}, {"family": "Albers", "given": "Julian", "initials": "J"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Rasti", "given": "Azita", "initials": "A"}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U"}, {"family": "Slipicevic", "given": "Ana", "initials": "A"}, {"family": "Mortusewicz", "given": "Oliver", "initials": "O", "orcid": "0000-0002-4290-4994", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6f546fe8f2c54824b942f7f88976e3bd.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}], "type": "journal article", "published": "2024-09-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "18", "issue": "9", "pages": "2179-2195", "issn-l": "1574-7891"}, "abstract": "The one-carbon metabolism enzyme bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is among the most overexpressed proteins across tumors and is widely recognized as a promising anticancer target. While MTHFD2 is mainly described as a mitochondrial protein, a new nuclear function is emerging. Here, we observe that nuclear MTHFD2 protein levels and association with chromatin increase following ionizing radiation (IR) in an ataxia telangiectasia mutated (ATM)- and DNA-dependent protein kinase (DNA-PK)-dependent manner. Furthermore, repair of IR-induced DNA double-strand breaks (DSBs) is delayed upon MTHFD2 knockdown, suggesting a role for MTHFD2 in DSB repair. In support of this, we observe impaired recruitment of replication protein A (RPA), reduced resection, decreased IR-induced DNA repair protein RAD51 homolog 1 (RAD51) levels and impaired homologous recombination (HR) activity in MTHFD2-depleted cells following IR. In conclusion, we identify a key role for MTHFD2 in HR repair and describe an interdependency between MTHFD2 and HR proficiency that could potentially be exploited for cancer therapy.", "doi": "10.1002/1878-0261.13645", "pmid": "38533616", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11467796"}], "notes": [], "created": "2026-08-20T06:26:58.460Z", "modified": "2026-08-20T06:26:58.641Z"}, {"entity": "publication", "iuid": "7eb2d82963424e0398052e67ec271b9c", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/7eb2d82963424e0398052e67ec271b9c.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/7eb2d82963424e0398052e67ec271b9c"}}, "title": "Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway.", "authors": [{"family": "Shen", "given": "Jianyu", "initials": "J"}, {"family": "Guill\u00e9n Mancina", "given": "Emilio", "initials": "E"}, {"family": "Chen", "given": "Shenyu", "initials": "S"}, {"family": "Manolakou", "given": "Theodora", "initials": "T", "orcid": "0000-0001-5284-6655", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7de36c6d31944ddd8616a9c79897d776.json"}}, {"family": "Gad", "given": "Helge", "initials": "H"}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U"}, {"family": "Sanjiv", "given": "Kumar", "initials": "K"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}], "type": "journal article", "published": "2024-05-25", "journal": {"title": "Oncogenesis", "issn": "2157-9024", "volume": "13", "issue": "1", "pages": "17", "issn-l": "2157-9024"}, "abstract": "The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-\u03b2 and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.", "doi": "10.1038/s41389-024-00518-1", "pmid": "38796460", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11127983"}, {"db": "pii", "key": "10.1038/s41389-024-00518-1"}], "notes": [], "created": "2026-08-20T08:48:37.318Z", "modified": "2026-08-20T08:48:37.435Z"}, {"entity": "publication", "iuid": "3420a1a676924ebd8de91145450af0cb", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3420a1a676924ebd8de91145450af0cb.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3420a1a676924ebd8de91145450af0cb"}}, "title": "Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence.", "authors": [{"family": "Fabbrizi", "given": "Maria Rita", "initials": "MR", "orcid": "0000-0002-5156-1575", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fd61af6ec662465994e9db4219a5c0bc.json"}}, {"family": "Nickson", "given": "Catherine M", "initials": "CM"}, {"family": "Hughes", "given": "Jonathan R", "initials": "JR", "orcid": "0000-0002-6420-2504", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/692e16d63afb4424834081d2887a10f2.json"}}, {"family": "Robinson", "given": "Emily A", "initials": "EA"}, {"family": "Vaidya", "given": "Karthik", "initials": "K", "orcid": "0009-0003-9378-8318", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/84b188c8461e4d3eae0d7bc1d6a833e2.json"}}, {"family": "Rubbi", "given": "Carlos P", "initials": "CP"}, {"family": "Kacperek", "given": "Andrzej", "initials": "A"}, {"family": "Bryant", "given": "Helen E", "initials": "HE", "orcid": "0000-0003-2720-7020", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a1cad482fd6b461898869f57465fe7d1.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Parsons", "given": "Jason L", "initials": "JL", "orcid": "0000-0002-5052-1125", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/37ab2de0a29248cf8865fd8be9da8318.json"}}], "type": "journal article", "published": "2024-02-17", "journal": {"title": "Cell Death Dis", "issn": "2041-4889", "volume": "15", "issue": "2", "pages": "150", "issn-l": "2041-4889"}, "abstract": "Complex DNA damage (CDD), containing two or more DNA lesions within one or two DNA helical turns, is a signature of ionising radiation (IR) and contributes significantly to the therapeutic effect through cell killing. The levels and complexity of CDD increases with linear energy transfer (LET), however, the specific cellular response to this type of DNA damage and the critical proteins essential for repair of CDD is currently unclear. We performed an siRNA screen of ~240 DNA damage response proteins to identify those specifically involved in controlling cell survival in response to high-LET protons at the Bragg peak, compared to low-LET entrance dose protons which differ in the amount of CDD produced. From this, we subsequently validated that depletion of 8-oxoguanine DNA glycosylase (OGG1) and poly(ADP-ribose) glycohydrolase (PARG) in HeLa and head and neck cancer cells leads to significantly increased cellular radiosensitivity specifically following high-LET protons, whilst no effect was observed after low-LET protons and X-rays. We subsequently confirmed that OGG1 and PARG are both required for efficient CDD repair post-irradiation with high-LET protons. Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation.", "doi": "10.1038/s41419-024-06541-9", "pmid": "38368415", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC10874437"}, {"db": "pii", "key": "10.1038/s41419-024-06541-9"}], "notes": [], "created": "2026-08-20T08:49:52.098Z", "modified": "2026-08-20T08:49:52.377Z"}, {"entity": "publication", "iuid": "71a0a3f15d0441dbabae996fb24e53ae", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/71a0a3f15d0441dbabae996fb24e53ae.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/71a0a3f15d0441dbabae996fb24e53ae"}}, "title": "Targeting MTHFD2 to Exploit Cancer-Specific Metabolism and the DNA Damage Response.", "authors": [{"family": "Ramos", "given": "Louise", "initials": "L", "orcid": "0000-0002-3808-6853", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/510846f4f3e644b49b8383e695fd4545.json"}}, {"family": "Henriksson", "given": "Martin", "initials": "M", "orcid": "0000-0002-2230-4887", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3f145ea339b44c45aebc45413b7da1ec.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Green", "given": "Alanna C", "initials": "AC", "orcid": "0000-0002-0175-1485", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4a8028ad77ff4912931fcda85a83ce00.json"}}], "type": "review", "published": "2024-01-02", "journal": {"title": "Cancer Res.", "issn": "1538-7445", "volume": "84", "issue": "1", "pages": "9-16", "issn-l": "0008-5472"}, "abstract": "The one-carbon folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is a promising therapeutic target in cancer. MTHFD2 is upregulated across numerous cancer types, promotes growth and metastasis of cancer, and correlates with poorer survival. Recent studies have developed small-molecule inhibitors to the isozymes MTHFD2 and MTHFD1 that show promise as anticancer agents through different mechanisms. This review discusses the current understanding of the function of MTHFD2 in cancer and the status of inhibitors for treating MTHFD2-overexpressing cancers.", "doi": "10.1158/0008-5472.CAN-23-1290", "pmid": "37922465", "labels": [], "xrefs": [{"db": "pii", "key": "730011"}], "notes": [], "created": "2026-08-20T12:11:09.658Z", "modified": "2026-08-20T12:11:09.815Z"}, {"entity": "publication", "iuid": "77475c1df233406b93598c917df16eeb", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/77475c1df233406b93598c917df16eeb.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/77475c1df233406b93598c917df16eeb"}}, "title": "Kinetic and structural characterization of human NUDIX hydrolases NUDT15 and NUDT18 as catalysts of isoprene pyrophosphate hydrolysis", "authors": [{"family": "Scaletti", "given": "Emma R", "initials": "ER", "orcid": "0000-0002-8741-8981", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/77be7f5d51564a75a753579e976c7c72.json"}}, {"family": "Unterlass", "given": "Judith E", "initials": "JE", "orcid": "0000-0002-7504-8338", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0aa7804a71ab4293aca5a78554737016.json"}}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Vallin", "given": "Karl S", "initials": "KS"}, {"family": "Kapsitidou", "given": "Despina", "initials": "D"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}, {"family": "Jemth", "given": "Ann Sofie", "initials": "AS", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/51f26d370fb74994b8e2b4fa1c9c2f7a.json"}}], "type": "posted-content", "published": "2023-11-29", "journal": {"issn-l": null}, "abstract": null, "doi": "10.1101/2023.11.29.569174", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T10:50:34.757Z", "modified": "2026-08-20T10:50:34.875Z"}, {"entity": "publication", "iuid": "711dd86fba2d433296c953225bd6f3fb", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/711dd86fba2d433296c953225bd6f3fb.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/711dd86fba2d433296c953225bd6f3fb"}}, "title": "Front Cover: Synthesis of Substituted Indazole Acetic Acids by N\u2212N Bond Forming Reactions (Eur. J. Org. Chem. 29/2023)", "authors": [{"family": "Odell", "given": "Luke R", "initials": "LR", "orcid": "0000-0001-7658-5103", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/49395660c6af4fce9ad0f7f8fc793744.json"}}, {"family": "Skillinghaug", "given": "Bobo", "initials": "B", "orcid": "0000-0002-8014-5757", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e4d7881ac9b6431d8eb0b0e319d9cd82.json"}}, {"family": "Matt", "given": "Christof", "initials": "C"}, {"family": "Wu", "given": "Peng", "initials": "P"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Desroses", "given": "Matthieu", "initials": "M", "orcid": "0000-0003-4152-3855", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b251e222615747a7822bf3cc26749cde.json"}}, {"family": "Llona\u2010Minguez", "given": "Sabin", "initials": "S"}, {"family": "Wallner", "given": "Olov", "initials": "O", "orcid": "0000-0002-6481-237X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3601a5a4d88f4452b6d1ac5f22c79d9f.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M", "orcid": "0000-0002-7073-8495", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bdce0df415d54e9d84a4fcbb4d1350e5.json"}}], "type": "journal-article", "published": "2023-08-00", "journal": {"title": "Eur. J. Org. Chem.", "issn": "1434-193X", "volume": "26", "issue": "29", "issn-l": "1099-0690"}, "abstract": null, "doi": "10.1002/ejoc.202300725", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T06:32:38.112Z", "modified": "2026-08-20T06:32:38.200Z"}, {"entity": "publication", "iuid": "bc6b2b40a7124560a96444df8e95484c", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/bc6b2b40a7124560a96444df8e95484c.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/bc6b2b40a7124560a96444df8e95484c"}}, "title": "Synthesis of Substituted Indazole Acetic Acids by N\u2212N Bond Forming Reactions", "authors": [{"family": "Odell", "given": "Luke R", "initials": "LR", "orcid": "0000-0001-7658-5103", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/49395660c6af4fce9ad0f7f8fc793744.json"}}, {"family": "Skillinghaug", "given": "Bobo", "initials": "B", "orcid": "0000-0002-8014-5757", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e4d7881ac9b6431d8eb0b0e319d9cd82.json"}}, {"family": "Matt", "given": "Christof", "initials": "C"}, {"family": "Wu", "given": "Peng", "initials": "P"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Desroses", "given": "Matthieu", "initials": "M", "orcid": "0000-0003-4152-3855", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b251e222615747a7822bf3cc26749cde.json"}}, {"family": "Llona\u2010Minguez", "given": "Sabin", "initials": "S"}, {"family": "Wallner", "given": "Olov", "initials": "O", "orcid": "0000-0002-6481-237X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3601a5a4d88f4452b6d1ac5f22c79d9f.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M", "orcid": "0000-0002-7073-8495", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bdce0df415d54e9d84a4fcbb4d1350e5.json"}}], "type": "journal-article", "published": "2023-08-00", "journal": {"title": "Eur. J. Org. Chem.", "issn": "1434-193X", "volume": "26", "issue": "29", "issn-l": "1099-0690"}, "abstract": null, "doi": "10.1002/ejoc.202300291", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T06:32:35.984Z", "modified": "2026-08-20T06:32:36.185Z"}, {"entity": "publication", "iuid": "722ce11b086b44db9af41560e1478a57", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/722ce11b086b44db9af41560e1478a57.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/722ce11b086b44db9af41560e1478a57"}}, "title": "NUDT22 promotes cancer growth through pyrimidine salvage.", "authors": [{"family": "Walter", "given": "Melanie", "initials": "M", "orcid": "0000-0003-3241-522X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4d7c13aca7b7474ead126c17d2d87160.json"}}, {"family": "Mayr", "given": "Florian", "initials": "F", "orcid": "0000-0002-0892-7076", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/18f5bceb8fbe4b3f90fb31191a89118b.json"}}, {"family": "Hanna", "given": "Bishoy M F", "initials": "BMF", "orcid": "0000-0001-7027-6553", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/61301102836e44d189f5628bb33c1335.json"}}, {"family": "Cookson", "given": "Victoria", "initials": "V"}, {"family": "Mortusewicz", "given": "Oliver", "initials": "O", "orcid": "0000-0002-4290-4994", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6f546fe8f2c54824b942f7f88976e3bd.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Herr", "given": "Patrick", "initials": "P", "orcid": "0000-0003-2945-966X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0140001cd2214241af0f5adc955321ae.json"}}], "type": "journal article", "published": "2023-04-00", "journal": {"title": "Oncogene", "issn": "1476-5594", "volume": "42", "issue": "16", "pages": "1282-1293", "issn-l": "0950-9232"}, "abstract": "The NUDIX hydrolase NUDT22 converts UDP-glucose into glucose-1-phosphate and the pyrimidine nucleotide uridine monophosphate but a biological significance for this biochemical reaction has not yet been established. Glucose-1-phosphate is an important metabolite for energy and biomass production through glycolysis and nucleotides required for DNA replication are produced through energetically expensive de novo or energy-efficient salvage pathways. Here, we describe p53-regulated pyrimidine salvage through NUDT22-dependent hydrolysis of UDP-glucose to maintain cancer cell growth and to prevent replication stress. NUDT22 expression is consistently elevated in cancer tissues and high NUDT22 expression correlates with worse survival outcomes in patients indicating an increased dependency of cancer cells to NUDT22. Furthermore, we show that NUDT22 transcription is induced after inhibition of glycolysis, MYC-mediated oncogenic stress, and DNA damage directly through p53. NUDT22-deficient cancer cells suffer from growth retardation, S-phase delay, and slower DNA replication fork speed. Uridine supplementation rescues replication fork progression and alleviates replication stress and DNA damage. Conversely, NUDT22 deficiency sensitizes cells to de novo pyrimidine synthesis inhibition in vitro and reduces cancer growth in vivo. In conclusion, NUDT22 maintains pyrimidine supply in cancer cells and depletion of NUDT22 leads to genome instability. Targeting NUDT22 therefore has high potential for therapeutic applications in cancer therapy.", "doi": "10.1038/s41388-023-02643-4", "pmid": "36871087", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC10101856"}, {"db": "pii", "key": "10.1038/s41388-023-02643-4"}], "notes": [], "created": "2026-08-20T08:48:33.235Z", "modified": "2026-08-20T08:48:33.467Z"}, {"entity": "publication", "iuid": "9093be9d25304416ae8c5998d9551ac6", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/9093be9d25304416ae8c5998d9551ac6.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/9093be9d25304416ae8c5998d9551ac6"}}, "title": "Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model.", "authors": [{"family": "Tanner", "given": "L", "initials": "L", "orcid": "0000-0003-0626-9820", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/981640c7635b47b2aca0380e88fb307f.json"}}, {"family": "Single", "given": "A B", "initials": "AB"}, {"family": "Bhongir", "given": "R K V", "initials": "RKV", "orcid": "0000-0001-6648-1781", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a31b3b22ce2a439e9185e10e23824d96.json"}}, {"family": "Heusel", "given": "M", "initials": "M", "orcid": "0000-0002-8506-530X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1be58c525be846cdb4ec2c66f5c8e2e1.json"}}, {"family": "Mohanty", "given": "T", "initials": "T", "orcid": "0000-0003-4593-9612", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/aebc0056f7634624a1d9b49349ecdd83.json"}}, {"family": "Karlsson", "given": "C A Q", "initials": "CAQ"}, {"family": "Pan", "given": "L", "initials": "L", "orcid": "0000-0003-2324-2144", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/125298170cc54ff1b710b0c13d3b1c95.json"}}, {"family": "Clausson", "given": "C-M", "initials": "CM"}, {"family": "Bergwik", "given": "J", "initials": "J"}, {"family": "Wang", "given": "K", "initials": "K"}, {"family": "Andersson", "given": "C K", "initials": "CK"}, {"family": "Oommen", "given": "R M", "initials": "RM"}, {"family": "Erjef\u00e4lt", "given": "J S", "initials": "JS"}, {"family": "Malmstr\u00f6m", "given": "J", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c89da9268a4f47a8a99fd62de451aaa7.json"}}, {"family": "Wallner", "given": "O", "initials": "O"}, {"family": "Boldogh", "given": "I", "initials": "I"}, {"family": "Helleday", "given": "T", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Kalder\u00e9n", "given": "C", "initials": "C"}, {"family": "Egesten", "given": "A", "initials": "A", "orcid": "0000-0001-5269-3433", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/63e0e8feadd341789778f04cd07cf020.json"}}], "type": "journal article", "published": "2023-02-06", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "14", "issue": "1", "pages": "643", "issn-l": "2041-1723"}, "abstract": "Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.", "doi": "10.1038/s41467-023-36314-5", "pmid": "36746968", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9902543"}, {"db": "pii", "key": "10.1038/s41467-023-36314-5"}], "notes": [], "created": "2026-08-20T08:52:35.313Z", "modified": "2026-08-20T08:52:35.614Z"}, {"entity": "publication", "iuid": "08aaf14158a140369f042374ecde45a3", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/08aaf14158a140369f042374ecde45a3.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/08aaf14158a140369f042374ecde45a3"}}, "title": "An Approach for Systems-Level Understanding of Prostate Cancer from High-Throughput Data Integration to Pathway Modeling and Simulation.", "authors": [{"family": "Mobashir", "given": "Mohammad", "initials": "M", "orcid": "0000-0002-5385-4048", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8e961b3a2fe94cb3acc1fa8f718cd97c.json"}}, {"family": "Turunen", "given": "S Pauliina", "initials": "SP", "orcid": "0000-0001-8060-9876", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5ca544f8f7314ccfaf87c365aba0996e.json"}}, {"family": "Izhari", "given": "Mohammad Asrar", "initials": "MA"}, {"family": "Ashankyty", "given": "Ibraheem Mohammed", "initials": "IM", "orcid": "0000-0002-6222-9674", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0731aaa25f51446fbcc5bb5045e5a36f.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Lehti", "given": "Kaisa", "initials": "K", "orcid": "0000-0001-9110-8719", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/613d944b4c8c4942b871ba87f580e53e.json"}}], "type": "journal article", "published": "2022-12-19", "journal": {"title": "Cells", "issn": "2073-4409", "volume": "11", "issue": "24", "issn-l": "2073-4409"}, "abstract": "To understand complex diseases, high-throughput data are generated at large and multiple levels. However, extracting meaningful information from large datasets for comprehensive understanding of cell phenotypes and disease pathophysiology remains a major challenge. Despite tremendous advances in understanding molecular mechanisms of cancer and its progression, current knowledge appears discrete and fragmented. In order to render this wealth of data more integrated and thus informative, we have developed a GECIP toolbox to investigate the crosstalk and the responsible genes'/proteins' connectivity of enriched pathways from gene expression data. To implement this toolbox, we used mainly gene expression datasets of prostate cancer, and the three datasets were GSE17951, GSE8218, and GSE1431. The raw samples were processed for normalization, prediction of differentially expressed genes, and the prediction of enriched pathways for the differentially expressed genes. The enriched pathways have been processed for crosstalk degree calculations for which number connections per gene, the frequency of genes in the pathways, sharing frequency, and the connectivity have been used. For network prediction, protein-protein interaction network database FunCoup2.0 was used, and cytoscape software was used for the network visualization. In our results, we found that there were enriched pathways 27, 45, and 22 for GSE17951, GSE8218, and GSE1431, respectively, and 11 pathways in common between all of them. From the crosstalk results, we observe that focal adhesion and PI3K pathways, both experimentally proven central for cellular output upon perturbation of numerous individual/distinct signaling pathways, displayed highest crosstalk degree. Moreover, we also observe that there were more critical pathways which appear to be highly significant, and these pathways are HIF1a, hippo, AMPK, and Ras. In terms of the pathways' components, GSK3B, YWHAE, HIF1A, ATP1A3, and PRKCA are shared between the aforementioned pathways and have higher connectivity with the pathways and the other pathway components. Finally, we conclude that the focal adhesion and PI3K pathways are the most critical pathways, and since for many other pathways, high-rank enrichment did not translate to high crosstalk degree, the global impact of one pathway on others appears distinct from enrichment.", "doi": "10.3390/cells11244121", "pmid": "36552885", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9777290"}, {"db": "pii", "key": "cells11244121"}], "notes": [], "created": "2026-08-20T13:40:09.571Z", "modified": "2026-08-20T13:40:09.816Z"}, {"entity": "publication", "iuid": "f1d5c63874ab42a299e12ca5c08eeb83", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/f1d5c63874ab42a299e12ca5c08eeb83.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/f1d5c63874ab42a299e12ca5c08eeb83"}}, "title": "Overexpressed c-Myc Sensitizes Cells to TH1579, a Mitotic Arrest and Oxidative DNA Damage Inducer.", "authors": [{"family": "Henriksson", "given": "Sofia", "initials": "S"}, {"family": "Calder\u00f3n-Monta\u00f1o", "given": "Jos\u00e9 Manuel", "initials": "JM", "orcid": "0000-0001-6845-797X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/06bf2684da93449381c951c32dc14703.json"}}, {"family": "Solvie", "given": "Daniel", "initials": "D", "orcid": "0000-0003-4529-667X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5557da3d375f4a81ac9c29d36875b7d4.json"}}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U", "orcid": "0000-0002-6372-1396", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8b6cab92fb2c4597a0c04777095f80db.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}], "type": "journal article", "published": "2022-11-29", "journal": {"title": "Biomolecules", "issn": "2218-273X", "volume": "12", "issue": "12", "issn-l": null}, "abstract": "Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras-expressing or -transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Several oncogenes induce replication stress, resulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment causes toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overexpressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but not by nucleoside supplementation. We conclude that the molecular toxicological mechanisms of how TH588 and TH1579 kill c-Myc overexpressing cells have several components and involve MTH1-independent proteasomal degradation of c-Myc itself, c-Myc-driven transcription and CDK activation.", "doi": "10.3390/biom12121777", "pmid": "36551206", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9775511"}, {"db": "pii", "key": "biom12121777"}], "notes": [], "created": "2026-08-20T13:38:42.021Z", "modified": "2026-08-20T13:38:42.136Z"}, {"entity": "publication", "iuid": "731ee047142a4f8cb2afa616fd06200d", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/731ee047142a4f8cb2afa616fd06200d.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/731ee047142a4f8cb2afa616fd06200d"}}, "title": "Targeting the DNA damage response and repair in cancer through nucleotide metabolism.", "authors": [{"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Rudd", "given": "Sean G", "initials": "SG", "orcid": "0000-0002-4368-3855", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d65643e96cfe4f3a98cf4f48225eac73.json"}}], "type": "journal article", "published": "2022-11-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "16", "issue": "21", "pages": "3792-3810", "issn-l": "1574-7891"}, "abstract": "The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1. \u00a9 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.", "doi": "10.1002/1878-0261.13227", "pmid": "35583750", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9627788"}], "notes": [], "created": "2026-08-20T06:26:48.146Z", "modified": "2026-08-20T06:26:48.211Z"}, {"entity": "publication", "iuid": "ad59b1b98d8c42d881dd45a6ac12c52a", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/ad59b1b98d8c42d881dd45a6ac12c52a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/ad59b1b98d8c42d881dd45a6ac12c52a"}}, "title": "Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM", "authors": [{"family": "Valerie", "given": "Nicholas C K", "initials": "NCK", "orcid": "0000-0002-9423-964X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/48bb9c8ab8a5465a8a4da1997f1af56d.json"}}, {"family": "Sanjiv", "given": "Kumar", 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"Langelier", "given": "Marie France", "initials": "MF", "orcid": "0000-0001-9815-1840", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/79beb7ce9d3b46528f35b1cf9038cf65.json"}}, {"family": "Rehling", "given": "Daniel", "initials": "D", "orcid": "0000-0002-8627-3469", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5aff0e51eb124b7183a9e752256288a4.json"}}, {"family": "Throup", "given": "Adam", "initials": "A", "orcid": "0000-0001-6512-8679", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1d7373aaa685464492b615ea4152b843.json"}}, {"family": "Desroses", "given": "Matthieu", "initials": "M", "orcid": "0000-0003-4152-3855", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b251e222615747a7822bf3cc26749cde.json"}}, {"family": "Onireti", "given": "Jacob", "initials": "J"}, {"family": "Wakchaure", "given": "Prasad", "initials": "P", "orcid": "0000-0003-2828-4642", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4d20f3f040894567b699c50b8b9e9fd4.json"}}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Bostr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0001-5252-4023", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6e6b3b2450f0498f9d0be4d9af615e89.json"}}, {"family": "Bevc", "given": "Luka", "initials": "L"}, {"family": "Benzi", "given": "Giorgia", "initials": "G"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}, {"family": "Pascal", "given": "John M", "initials": "JM", "orcid": "0000-0002-2714-4317", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/82a900bd9df84da594641911c65750f1.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Page", "given": "Brent D G", "initials": "BDG", "orcid": "0000-0002-2101-1329", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6cb0faad98c34cf7b9d4f60d03274727.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d77b74fe6e7d44f4800fe8bb4404ad8f.json"}}], "type": "posted-content", "published": "2022-09-19", "journal": {"issn-l": null}, "abstract": null, "doi": "10.1101/2022.09.19.505646", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T10:14:18.579Z", "modified": "2026-08-20T10:14:19.029Z"}, {"entity": "publication", "iuid": "b1e3052a77514a259909d4d737df4580", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/b1e3052a77514a259909d4d737df4580.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/b1e3052a77514a259909d4d737df4580"}}, "title": "Overexpressed C-Myc Sensitize Cells to TH1579, an Mitotic Arrest and Oxidative DNA Damage Inducer", "authors": [{"family": "Henriksson", "given": "Sofia", "initials": "S"}, {"family": "Calder\u00f3n-Monta\u00f1o", "given": "Jos\u00e9 Manuel", "initials": "JM", "orcid": "0000-0001-6845-797X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/06bf2684da93449381c951c32dc14703.json"}}, {"family": "Solvie", "given": "Daniel", "initials": "D"}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U", "orcid": "0000-0002-6372-1396", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8b6cab92fb2c4597a0c04777095f80db.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}], "type": "posted-content", "published": "2022-08-22", "journal": {"issn-l": null}, "abstract": null, "doi": "10.20944/preprints202208.0369.v1", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T12:56:32.667Z", "modified": "2026-08-20T12:56:32.691Z"}, {"entity": "publication", "iuid": "5c5bfa7eea964cf7961bdec3453b5d92", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/5c5bfa7eea964cf7961bdec3453b5d92.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/5c5bfa7eea964cf7961bdec3453b5d92"}}, "title": "Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.", "authors": [{"family": "Michel", "given": "Maurice", "initials": "M", "orcid": "0000-0003-3261-2493", "researcher": {"href": 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"https://publications-affiliated.scilifelab.se/researcher/2aeb36f9611f4c03883b8def30565da1.json"}}, {"family": "Ortis", "given": "Florian", "initials": "F", "orcid": "0000-0002-0458-5187", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a2e13b716bc349eb9dac083d7f801549.json"}}, {"family": "Sch\u00f6mberg", "given": "Fritz", "initials": "F", "orcid": "0000-0003-0092-0627", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7f10b06057e94d03a44967cce431c1a8.json"}}, {"family": "Loseva", "given": "Olga", "initials": "O"}, {"family": "Stewart", "given": "Josephine", "initials": "J"}, {"family": "D'Arcy-Evans", "given": "Nicholas", "initials": "N"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Henriksson", "given": "Martin", "initials": "M"}, {"family": "Michel", "given": "Dana", "initials": "D"}, {"family": "de Ory", "given": "Ana", "initials": "A"}, {"family": "Acero", "given": "Lucia", "initials": "L", "orcid": "0000-0001-8101-5412", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/af80832b8d8c4019bea17c15fa7651e2.json"}}, {"family": "Calvete", "given": "Oriol", "initials": "O", "orcid": "0000-0002-2623-2876", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0ee0251167344b24b97b971b8c750795.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M", "orcid": "0000-0002-7073-8495", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bdce0df415d54e9d84a4fcbb4d1350e5.json"}}, {"family": "Hertweck", "given": "Christian", "initials": "C", "orcid": "0000-0002-0367-337X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2b1f3fa37a7d4378b06381c2e68a10cb.json"}}, {"family": "Vilotijevic", "given": "Ivan", "initials": "I", "orcid": "0000-0001-6199-0632", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/eec3fc0f230046ccbe7ff46b2da70792.json"}}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C", "orcid": "0000-0001-7004-7048", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e9c7121a5e14414b8bace2708e8add2f.json"}}, {"family": "Osorio", "given": "Ana", "initials": "A", "orcid": "0000-0001-8124-3984", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6ecd4cc9c17d43009703efb95d979e09.json"}}, {"family": "Perona", "given": "Rosario", "initials": "R", "orcid": "0000-0002-2973-5153", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5b116837f5c346d49e70ad5eb28d7afb.json"}}, {"family": "Stolz", "given": "Alexandra", "initials": "A", "orcid": "0000-0002-3340-439X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4bde36f21953479a8762c1c858b4c451.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}, {"family": "Berglund", "given": "Ulrika Warpman", "initials": "UW", "orcid": "0000-0002-6372-1396", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8b6cab92fb2c4597a0c04777095f80db.json"}}, {"family": "de Vega", "given": "Miguel", "initials": "M", "orcid": "0000-0003-1285-7549", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6196fa790b4645c3acef45a87cdac3d0.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}], "type": "journal article", "published": "2022-06-24", "journal": {"title": "Science (New York, N.Y.)", "issn": "1095-9203", "volume": "376", "issue": "6600", "pages": "1471-1476", "issn-l": "0036-8075"}, "abstract": "Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed \u03b2,\u03b4-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.", "doi": "10.1126/science.abf8980", "pmid": "35737787", "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T11:59:29.051Z", "modified": "2026-08-20T11:59:30.134Z"}, {"entity": "publication", "iuid": "aec0479422f7499893a6085f86433e56", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/aec0479422f7499893a6085f86433e56.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/aec0479422f7499893a6085f86433e56"}}, "title": "OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice", "authors": [{"family": "Tanner", "given": "Lloyd", "initials": "L", "orcid": "0000-0003-0626-9820", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/981640c7635b47b2aca0380e88fb307f.json"}}, {"family": "Bergwik", "given": "Jesper", "initials": "J"}, {"family": "Bhongir", "given": "Ravi KV", "initials": "RK"}, {"family": "Pan", "given": "Lang", "initials": "L"}, {"family": "Dong", "given": "Caijuan", "initials": "C"}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Boldogh", "given": "Istvan", "initials": "I"}, {"family": "Adner", "given": "Mikael", "initials": "M"}, {"family": "Egesten", "given": "Arne", "initials": "A", "orcid": "0000-0001-5269-3433", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/63e0e8feadd341789778f04cd07cf020.json"}}], "type": "posted-content", "published": "2022-05-19", "journal": {"issn-l": null}, "abstract": null, "doi": "10.1101/2022.05.17.492235", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T10:11:14.539Z", "modified": "2026-08-20T10:11:14.566Z"}, {"entity": "publication", "iuid": "bad6d71e7fb0452197c9d75414250a45", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/bad6d71e7fb0452197c9d75414250a45.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/bad6d71e7fb0452197c9d75414250a45"}}, "title": "MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells.", "authors": [{"family": "Karsten", "given": "Stella", "initials": "S", "orcid": "0000-0001-6191-4314", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3a27ec21e4a34600aa24a7213372e19c.json"}}, {"family": "Fiskesund", "given": "Roland", "initials": "R"}, {"family": "Zhang", "given": "Xing-Mei", "initials": "XM"}, {"family": "Marttila", "given": "Petra", "initials": "P", "orcid": "0000-0002-0115-8067", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4ed95784f80a45d9abb072fbb74fc225.json"}}, {"family": "Sanjiv", "given": "Kumar", "initials": "K"}, {"family": "Pham", "given": "Therese", "initials": "T"}, {"family": "Rasti", "given": "Azita", "initials": "A"}, {"family": "Br\u00e4utigam", "given": "Lars", "initials": "L"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Marcusson-St\u00e5hl", "given": "Maritha", "initials": "M"}, {"family": "Sandman", "given": "Carolina", "initials": "C"}, {"family": "Platzack", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Harris", "given": "Robert A", "initials": "RA"}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C"}, {"family": "Cederbrant", "given": "Karin", "initials": "K"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U"}], "type": "journal article", "published": "2022-01-00", "journal": {"title": "Cell Death Differ.", "issn": "1476-5403", "volume": "29", "issue": "1", "pages": "246-261", "issn-l": "1350-9047"}, "abstract": "T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not up-regulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1low phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1high and MTH1low activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.", "doi": "10.1038/s41418-021-00854-4", "pmid": "34453118", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8738733"}, {"db": "pii", "key": "10.1038/s41418-021-00854-4"}], "notes": [], "created": "2026-08-20T08:49:19.589Z", "modified": "2026-08-20T08:49:19.664Z"}, {"entity": "publication", "iuid": "d2b4c79719e4482eb9fb11a396b850be", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/d2b4c79719e4482eb9fb11a396b850be.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/d2b4c79719e4482eb9fb11a396b850be"}}, "title": "Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion.", "authors": [{"family": "Hansel", "given": "Christine", "initials": "C"}, {"family": "Hlouschek", "given": "Julian", "initials": "J"}, {"family": "Xiang", "given": "Kexu", "initials": "K", "orcid": "0000-0001-8184-8721", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0800644c49954771a8821db0699f8ddd.json"}}, {"family": "Melnikova", "given": "Margarita", "initials": "M"}, {"family": "Thomale", "given": "Juergen", "initials": "J"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Jendrossek", "given": "Verena", "initials": "V", "orcid": "0000-0003-1058-2107", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c6b90c53840342bb85adf793901cd3b3.json"}}, {"family": "Matschke", "given": "Johann", "initials": "J", "orcid": "0000-0003-4878-8741", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/372c8d8766314f31ab29b21255de9c60.json"}}], "type": "journal article", "published": "2021-11-05", "journal": {"title": "Cells", "issn": "2073-4409", "volume": "10", "issue": "11", "issn-l": "2073-4409"}, "abstract": "Tumor hypoxia and hypoxic adaptation of cancer cells represent major barriers to successful cancer treatment. We revealed that improved antioxidant capacity contributes to increased radioresistance of cancer cells with tolerance to chronic-cycling severe hypoxia/reoxygenation stress. We hypothesized, that the improved tolerance to oxidative stress will increase the ability of cancer cells to cope with ROS-induced damage to free deoxy-nucleotides (dNTPs) required for DNA replication and may thus contribute to acquired resistance of cancer cells in advanced tumors to antineoplastic agents inhibiting the nucleotide-sanitizing enzyme MutT Homologue-1 (MTH1), ionizing radiation (IR) or both. Therefore, we aimed to explore potential differences in the sensitivity of cancer cells exposed to acute and chronic-cycling hypoxia/reoxygenation stress to the clinically relevant MTH1-inhibitor TH1579 (Karonudib) and to test whether a multi-targeting approach combining the glutathione withdrawer piperlongumine (PLN) and TH1579 may be suited to increase cancer cell sensitivity to TH1579 alone and in combination with IR. Combination of TH1579 treatment with radiotherapy (RT) led to radiosensitization but was not able to counteract increased radioresistance induced by adaptation to chronic-cycling hypoxia/reoxygenation stress. Disruption of redox homeostasis using PLN sensitized anoxia-tolerant cancer cells to MTH1 inhibition by TH1579 under both normoxic and acute hypoxic treatment conditions. Thus, we uncover a glutathione-driven compensatory resistance mechanism towards MTH1-inhibition in form of increased antioxidant capacity as a consequence of microenvironmental or therapeutic stress.", "doi": "10.3390/cells10113040", "pmid": "34831264", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8616547"}, {"db": "pii", "key": "cells10113040"}], "notes": [], "created": "2026-08-20T13:40:06.390Z", "modified": "2026-08-20T13:40:06.587Z"}, {"entity": "publication", "iuid": "e37a961ddf5c4d83b2ab298494d17052", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e37a961ddf5c4d83b2ab298494d17052.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e37a961ddf5c4d83b2ab298494d17052"}}, "title": "Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma.", "authors": [{"family": "van den Boogaard", "given": "Marlinde L", "initials": "ML", "orcid": "0000-0002-3713-5270", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3042f6038437434b88360c13945bbe59.json"}}, {"family": "Oka", "given": "Rurika", "initials": "R", "orcid": "0000-0003-4107-7250", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/778b1be91d2244189ca425a5895735a2.json"}}, {"family": "Hakkert", "given": "Anne", "initials": "A"}, {"family": "Schild", "given": "Linda", "initials": "L"}, {"family": "Ebus", "given": "Marli E", "initials": "ME", "orcid": "0000-0002-8181-8941", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b81e10b8a23649cfafae6ca45e7f3014.json"}}, {"family": "van Gerven", "given": "Michael R", "initials": "MR", "orcid": "0000-0001-5241-8810", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f062c944ea324ae699d0225b365a790b.json"}}, {"family": "Zwijnenburg", "given": "Danny A", "initials": "DA"}, {"family": "Molenaar", "given": "Piet", "initials": "P"}, {"family": "Hoyng", "given": "Lieke L", "initials": "LL"}, {"family": "Dolman", "given": "M Emmy M", "initials": "MEM"}, {"family": "Essing", "given": "Anke H W", "initials": "AHW"}, {"family": "Koopmans", "given": "Bianca", "initials": "B"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}, {"family": "Drost", "given": "Jarno", "initials": "J", "orcid": "0000-0002-2941-6179", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b01477f3bad04636b42ddd5b5ace6cb1.json"}}, {"family": "van Boxtel", "given": "Ruben", "initials": "R", "orcid": "0000-0003-1285-2836", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2d492d3f71bc4586bd0398ef99f03a5b.json"}}, {"family": "Versteeg", "given": "Rogier", "initials": "R", "orcid": "0000-0001-7172-0388", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5ecd554eb81c41d29c3667af93a761d5.json"}}, {"family": "Koster", "given": "Jan", "initials": "J", "orcid": "0000-0002-0890-7585", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/cbc4487331414b64ab7e95a823e09cbb.json"}}, {"family": "Molenaar", "given": "Jan J", "initials": "JJ", "orcid": "0000-0002-2007-0431", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0636796fc05c4b0f9ce5df0ce0f8ff6e.json"}}], "type": "journal article", "published": "2021-09-07", "journal": {"title": "Proc. Natl. Acad. Sci. U.S.A.", "issn": "1091-6490", "volume": "118", "issue": "36", "issn-l": "0027-8424"}, "abstract": "Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution.", "doi": "10.1073/pnas.2007898118", "pmid": "34479993", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8433536"}, {"db": "pii", "key": "2007898118"}], "notes": [], "created": "2026-08-20T09:30:46.001Z", "modified": "2026-08-20T09:30:46.407Z"}, {"entity": "publication", "iuid": "a5bfa02ae6314b9e807126381f77a770", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a5bfa02ae6314b9e807126381f77a770.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a5bfa02ae6314b9e807126381f77a770"}}, "title": "Pol\u03b8 inhibitors unchained.", "authors": [{"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/385586c159494955a9a72c3381e3ad47.json"}}], "type": "journal article", "published": "2021-06-00", "journal": {"title": "Nat Cancer", "issn": "2662-1347", "volume": "2", "issue": "6", "pages": "581-583", "issn-l": null}, "abstract": null, "doi": "10.1038/s43018-021-00225-5", "pmid": "35121938", "labels": [], "xrefs": [{"db": "pii", "key": "10.1038/s43018-021-00225-5"}], "notes": [], "created": "2026-08-20T09:26:05.824Z", "modified": "2026-08-20T09:26:05.884Z"}, {"entity": "publication", "iuid": "565c8ebd51d44e2ebe08d32f106f0c85", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/565c8ebd51d44e2ebe08d32f106f0c85.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/565c8ebd51d44e2ebe08d32f106f0c85"}}, "title": "MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells", "authors": [{"family": "Gad", "given": "Helge", "initials": "H"}, 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