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.

中文翻译：

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单碳代谢酶MTHFD2促进电离辐射后的切除和同源重组

单碳代谢酶双功能亚甲基四氢叶酸脱氢酶/环水解酶 2 (MTHFD2) 是肿瘤中过度表达最多的蛋白质之一，被广泛认为是有前途的抗癌靶点。虽然 MTHFD2 主要被描述为一种线粒体蛋白，但一种新的核功能正在出现。在这里，我们观察到核 MTHFD2 蛋白水平以及与染色质的关联在电离辐射 (IR) 后以共济失调毛细血管扩张突变 (ATM) 和 DNA 依赖性蛋白激酶 (DNA-PK) 依赖性方式增加。此外，IR 诱导的 DNA 双链断裂 (DSB) 的修复会延迟甲基四氢呋喃2敲低，表明 MTHFD2 在 DSB 修复中发挥作用。为了支持这一点，我们观察到复制蛋白 A (RPA) 的募集受损、切除减少、IR 诱导的 DNA 修复蛋白 RAD51 同源物 1 (RAD51) 水平降低以及同源重组 (HR) 活性受损甲基四氢呋喃2‐IR后细胞耗尽。总之，我们确定了 MTHFD2 在 HR 修复中的关键作用，并描述了 MTHFD2 和 HR 熟练程度之间的相互依赖性，有可能用于癌症治疗。