Oncometabolite fumarate impairs ATR-CHK1 signaling by succinating RPA1 in Fumarate Hydratase-deficient renal cell carcinoma cells.

ABSTRACT: Abnormal accumulation of oncometabolite fumarate drives susceptibility in fumarate hydratase-deficient renal cell carcinoma (FH-dRCC), but the precise mechanisms remain not fully understood. In this study, we demonstrate that high fumarate levels impair activation of ATR-CHK1 signaling in response to replication stress and DNA damage. Mechanistically, fumarate modifies RPA1, an essential factor for ATR-CHK1 activation through succination, a post-translational modification. Succination of RPA1 occurs mainly at cysteine residues 481 and 486, which reduces its binding affinity for single-stranded DNA (ssDNA). RPA1 succination leads to deficient recruitment of TOPBP1 to ssDNA, resulting in attenuated CHK1 activation and defective cell cycle arrest in response to DNA damage. Succinated RPA1 com

SUBMITTER: Liu N 

PROVIDER: S-EPMC12713586 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature