Nature: Tumor metabolites disrupt chromatin signals and inhibit DNA repair

Metabolic disorders and the destruction of genomic integrity are the main markers of cancerIncreased levels of metabolites 2-hydroxypronoric acid, semacid and fumatate are found in human malignancies due to somatic cell mutations in the isofrate dehydrogenase-1 or -2 (IDH1 or IDH2) genes, or variants of the fumatorhydrate hydrate (FH) and amber dehydrogenase genes (SDHA, SDHB, SDHC and SDDHD)Recent work has led to an unexpected link between these metabolites and DNA repair, which inhibits the path of homologous dependence (HDR) and makes cells sensitive to inhibitors of (ADP-ribose) polymerase (PARP)ParP inhibitors are undergoing clinical trialsHowever, we still know very little about how these tumor metabolites inhibit HDR mechanismsRecently, researchers identified ways in which these metabolites destroy DNA repairThe researchers showed that the inhibition of lysine demethylase KDM4B induced by anti-cancer metabolites led to abnormal hypermethylation of histone 3 lysine 9 (H3K9) at sites around DNA fractures, masking local H3K9 trimethylating signals critical to the correct execution of HDRAs a result, the recruitment of two key near-end HDR factors, TIP60 and ATM, is significantly impaired at DNA fractures, end excision is reduced, and recruitment of downstream repair factors is reducedThese findings provide a mechanism basis for tumor metabolite-induced HDR inhibition and can guide effective strategies for using these defects to obtain therapeutic benefits