The one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation.
Mol Oncol
; 18(9): 2179-2195, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-38533616
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Radiation, Ionizing
/
Homologous Recombination
/
Multifunctional Enzymes
/
Aminohydrolases
/
Methylenetetrahydrofolate Dehydrogenase (NADP)
Limits:
Humans
Language:
En
Journal:
Mol Oncol
Year:
2024
Document type:
Article