The one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation

Petra Marttila, Nadilly Bonagas, Christina Chalkiadaki, Hannah Stigsdotter, Korbinian Schelzig, Jianyu Shen, Crystal M. Farhat, Amber Hondema, Julian Albers, Elisée Wiita, Azita Rasti, Ulrika Warpman Berglund, Ana Slipicevic, Oliver Mortusewicz, Thomas Helleday*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
JournalMolecular Oncology
Early online date27 Mar 2024
DOIs
Publication statusE-pub ahead of print - 27 Mar 2024
Externally publishedYes

Keywords

  • DSB repair
  • homologous recombination
  • ionizing radiation
  • MTHFD2

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