The one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation.
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Marttila P, Bonagas N, Chalkiadaki C, Stigsdotter H, Schelzig K, Shen J, Farhat CM, Hondema A, Albers J, Wiita E, Rasti A, Warpman Berglund U, Slipicevic A, Mortusewicz O, Helleday T
Mol Oncol 18 (9) 2179-2195 [2024-09-00; online 2024-03-27]
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.
PubMed 38533616
DOI 10.1002/1878-0261.13645
Crossref 10.1002/1878-0261.13645