{"entity": "publication", "iuid": "55417aac716045a293c8648701cec3fd", "timestamp": "2026-10-05T01:21:57.300Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/55417aac716045a293c8648701cec3fd.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/55417aac716045a293c8648701cec3fd"}}, "title": "Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1.", "authors": [{"family": "Hank", "given": "Emily C", "initials": "EC"}, {"family": "D'Arcy-Evans", "given": "Nicholas D", "initials": "ND"}, {"family": "Scaletti", "given": "Emma Rose", "initials": "ER"}, {"family": "Ben\u00edtez-Buelga", "given": "Carlos", "initials": "C"}, {"family": "Wallner", "given": "Olov", "initials": "O"}, {"family": "Ortis", "given": "Florian", "initials": "F"}, {"family": "Zhou", "given": "Kaixin", "initials": "K"}, {"family": "Meng", "given": "Liuzhen", "initials": "L"}, {"family": "Del Prado", "given": "Alicia", "initials": "A", "orcid": "0000-0002-5480-0367", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7625321e94ab4cb5ba256de247cd0fcd.json"}}, {"family": "Calvo", "given": "Patricia", "initials": "P"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Nierlin", "given": "Karen", "initials": "K"}, {"family": "Ko\u0161enina", "given": "Sara", "initials": "S"}, {"family": "Kr\u00e4mer", "given": "Andreas", "initials": "A"}, {"family": "Eddershaw", "given": "Alice", "initials": "A"}, {"family": "Kehler", "given": "Mario", "initials": "M"}, {"family": "Long", "given": "Maeve", "initials": "M"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS"}, {"family": "Dawson", "given": "Holly", "initials": "H"}, {"family": "Stewart", "given": "Josephine", "initials": "J"}, {"family": "Dickey", "given": "Adam", "initials": "A"}, {"family": "Astorga", "given": "Mikhael E", "initials": "ME"}, {"family": "Varga", "given": "Marek", "initials": "M"}, {"family": "Homan", "given": "Evert J", "initials": "EJ", "orcid": "0000-0002-9057-1848", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3a68aa16414c4c159c52a5e75d5537c1.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Knapp", "given": "Stefan", "initials": "S", "orcid": "0000-0001-5995-6494", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b6025ceada8d460aa28aa3175e423853.json"}}, {"family": "Sastre", "given": "Leandro", "initials": "L"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P"}, {"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"}, {"family": "Michel", "given": "Maurice", "initials": "M", "orcid": "0000-0003-3261-2493", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6f4696e361fe4aa3823d263674d1a498.json"}}], "type": "journal article", "published": "2026-01-14", "journal": {"title": "RSC Chem Biol", "issn": "2633-0679", "volume": "7", "issue": "1", "pages": "169-181", "issn-l": null}, "abstract": "Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with an abasic (AP) site base excision repair intermediate. For 8-oxoguanine DNA glycosylase 1 (OGG1), cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair in DNA. Evolution has led OGG1 to use a product-assisted catalysis approach, where the excised 8-oxoG acts as a Br\u00f8nsted base for cleavage of a Schiff base intermediate. However, the physicochemical properties of 8-oxoG significantly limit the inherent enzymatic turnover leading to a weak, cellularly absent, AP lyase activity. We hypothesized that chemical synthesis of purine analogues enables access to complex structures that are suitable as product-like catalysts. Herein, the nucleobase landscape is profiled for its potential to increase OGG1 Schiff base cleavage. 8-Substituted 6-thioguanines emerge as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by \u03b2-elimination. This effectively broadens the enzymatic substrate scope of OGG1, shaping a complete, artificial AP-lyase function. In addition, a second class of compounds, 6-substituted pyrazolo-[3,4-d]-pyrimidines, stimulate OGG1 function at high pH, while thioguanines govern enzymatic control at acidic pH. This enables up to 20-fold increased enzyme turnover and a de novo OGG1 \u03b2-elimination in conditions commonly not tolerated. The tool compounds employed here are non-toxic in cells and stimulate the repair of AP sites through a natural, APE1 dependent pathway, as opposed to previously reported \u03b2,\u03b4-lyase stimulator TH10785.", "doi": "10.1039/d4cb00323c", "pmid": "41195166", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12584757"}, {"db": "pii", "key": "d4cb00323c"}], "notes": [], "created": "2026-10-01T08:27:16.769Z", "modified": "2026-10-01T08:27:16.841Z"}