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

Area of Science:

• Molecular Biology
• Cancer Research
• DNA Repair Mechanisms

Background:

• Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is a key enzyme in one-carbon metabolism, overexpressed in tumors.
• MTHFD2 is primarily known as a mitochondrial protein, but emerging evidence suggests novel nuclear functions.

Purpose of the Study:

• To investigate the nuclear role of MTHFD2 in response to ionizing radiation (IR).
• To determine MTHFD2's involvement in the repair of DNA double-strand breaks (DSBs).

Main Methods:

• Observation of nuclear MTHFD2 levels and chromatin association post-IR.
• Assessment of DNA double-strand break (DSB) repair kinetics in MTHFD2-depleted cells.
• Analysis of key DNA repair protein recruitment and homologous recombination (HR) activity.

Main Results:

• Nuclear MTHFD2 levels and chromatin association increase after IR in an ATM- and DNA-PK-dependent manner.
• MTHFD2 knockdown delays IR-induced DSB repair.
• MTHFD2 depletion impairs replication protein A (RPA) recruitment, reduces DNA resection, decreases RAD51 levels, and inhibits homologous recombination (HR) activity.

Conclusions:

• MTHFD2 plays a critical role in homologous recombination (HR) repair of DNA double-strand breaks.
• An interdependency exists between MTHFD2 function and HR proficiency, presenting a potential therapeutic vulnerability in cancer.