Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
One-carbon Therapeutics AB, Stockholm, Sweden.
Mol Oncol. 2024 Sep;18(9):2179-2195. doi: 10.1002/1878-0261.13645. Epub 2024 Mar 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.
一碳代谢酶双功能亚甲基四氢叶酸脱氢酶/环水合酶 2（MTHFD2）在肿瘤中是表达过度的蛋白之一，被广泛认为是一种很有前途的抗癌靶标。虽然 MTHFD2 主要被描述为一种线粒体蛋白，但它的一种新的核功能正在出现。在这里，我们观察到，在有 ATM 和 DNA 依赖性蛋白激酶（DNA-PK）依赖性的情况下，电离辐射（IR）后，核 MTHFD2 蛋白水平及其与染色质的结合增加。此外，MTHFD2 敲低后，IR 诱导的 DNA 双链断裂（DSB）的修复被延迟，表明 MTHFD2 在 DSB 修复中起作用。支持这一点，我们观察到在 MTHFD2 耗尽的细胞中，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，同源重组（HR）活性受损。总之，我们确定了 MTHFD2 在 HR 修复中的关键作用，并描述了 MTHFD2 与 HR 效率之间的相互依存关系，这可能为癌症治疗提供潜在的靶点。
