D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming.

ABSTRACT: Cancer-associated mutations in IDH are associated with multiple types of human malignancies, which exhibit distinctive metabolic reprogramming, production of oncometabolite D-2-HG, and shifted epigenetic landscape. IDH mutated malignancies are signatured with "BRCAness", highlighted with the sensitivity to DNA repair inhibitors and genotoxic agents, although the underlying molecular mechanism remains elusive. In the present study, we demonstrate that D-2-HG impacts the chromatin conformation adjustments, which are associated with DNA repair process. Mechanistically, D-2-HG diminishes the chromatin interactions in the DNA damage regions via revoking CTCF binding. The hypermethylation of cytosine, resulting from the suppression of TET1 and TET2 activities by D-2-HG, contributes to the dissoc

SUBMITTER: Lang F 

PROVIDER: S-EPMC11806014 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature