{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:11:37Z","timestamp":1792638697013,"version":"4.5.0"},"reference-count":48,"publisher":"Wiley","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2015\u201000162"],"award-info":[{"award-number":["2015\u201000162"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["21\u20101490"],"award-info":[{"award-number":["21\u20101490"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"abstract":"<jats:p>The one\u2010carbon 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)\u2010 and DNA\u2010dependent protein kinase (DNA\u2010PK)\u2010dependent manner. Furthermore, repair of IR\u2010induced DNA double\u2010strand breaks (DSBs) is delayed upon <jats:italic>MTHFD2<\/jats:italic> 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\u2010induced DNA repair protein RAD51 homolog 1 (RAD51) levels and impaired homologous recombination (HR) activity in <jats:italic>MTHFD2<\/jats:italic>\u2010depleted 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.<\/jats:p>","DOI":"10.1002\/1878-0261.13645","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T08:37:06Z","timestamp":1711528626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The one\u2010carbon metabolic enzyme <scp>MTHFD2<\/scp> promotes resection and homologous recombination after ionizing radiation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0115-8067","authenticated-orcid":false,"given":"Petra","family":"Marttila","sequence":"first","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology\u2010Pathology Karolinska Institutet  Solna 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Department of Oncology\u2010Pathology Karolinska Institutet  Solna Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyu","family":"Shen","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology\u2010Pathology Karolinska Institutet  Solna Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal M.","family":"Farhat","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology\u2010Pathology Karolinska Institutet  Solna Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Hondema","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Oncology\u2010Pathology Karolinska Institutet  Solna Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Albers","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of 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