Oncometabolite D-2-Hydroxyglutarate Disrupts Chromatin Topology Impairing DNA Repair

D-2-hydroxyglutarate (D-2-HG) is an abnormal metabolite produced in high concentrations in cancers with isocitrate dehydrogenase (IDH) mutations, such as glioma, acute myeloid leukemia, and chondrosarcoma. The IDH mutant enzyme exhibit neomorphic activity, driving the production of D-2-HG, which induces a unique oncogenic phenotype, characterized by genome-wide hypermethylation, reprogrammed metabolic landscape, and impaired DNA repair. Although these alterations contribute to tumor progression and increase therapeutic vulnerabilities, the exact molecular mechanisms linking D-2-HG to impaired DNA repair remain elusive. In the present study, we explore how D-2-HG affects chromatin structure to impair the DNA repair pathway, focusing specifically on homologous recombination (HR). We demonstrate that D-2-HG inhibits TET (ten-eleven translocation) methylcytosine dioxygenase activity, leading to widespread CpG island hypermethylation. This epigenetic modification dissociates the chromatin architectural protein CTCF (CCCTC-binding factor) from CpG-rich DNA regions. The loss of CTCF binding disrupts higher-order chromatin contacts critical for maintaining the structural integrity at the DNA damage sites. Consequently, key HR repair proteins, such as BRCA2 and RAD51, fail to be recruited to sites of DNA damage sites, significantly impairing HR efficiency. Our findings provide mechanistic insights into how the cancer metabolic signature leads to DNA repair deficiency, mediated by D-2-HG-induced chromatin alterations. The disruption of chromatin topology and loss of CTCF-mediated loops extrusion at DNA damage sites abolish effective DNA repair signaling, indicating a therapeutic vulnerability in IDH-mutant cells. Our study suggests that IDH-mutant tumors may be particularly susceptible to DNA repair inhibitors, such as PARP inhibitors, or other agents that further compromise HR repair. Citation Format: Fengchao Lang, Karambir Kaur, Chunzhang Yang. Oncometabolite D-2-hydroxyglutarate impairs homologous recombination by disrupting chromatin topology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 522.