Abstract
Metabolites produced in cancer cells interfered with resolution of DNA double-strand breaks.
Major Finding: Metabolites produced in cancer cells interfered with resolution of DNA double-strand breaks.
Mechanism: These metabolites inhibited a histone demethylase, affecting recruitment of DNA-repair factors.
Impact: This reveals a mechanism underlying the link between faulty DNA repair and metabolism in cancer.
DNA-repair deficiencies leading to disrupted genomic integrity and metabolic disturbances both occur in cancer, and recent work has revealed a possible link between faulty homology-dependent repair (HDR) and metabolites produced in cancer cells (oncometabolites). In an investigation of the mechanism underlying this phenomenon, Sulkowski and colleagues discovered that there was a direct connection between the presence of the oncometabolites 2-hydroxyglutarate, fumarate, or succinate in cells and defects in HDR. Addition of these oncometabolites to cells caused an increase in DNA double-strand breaks (DSB), which are common in HDR-deficient cells, along with a decrease in RAD51-containing DNA-repair foci following exposure to ionizing radiation. These results imply that the tested oncometabolites directly interfered with HDR. In normal cells, production of DNA DSBs led to a rapid increase in histone 3 lysine residue 9 trimethylation (H3K9me3) at the break site, and this caused recruitment of DNA-repair factors. First to be recruited were TIP60 and MRE11, which activated ATM and subsequently led to recruitment of RPA followed by BRCA1 and RAD51. However, in cells with elevated levels of oncometabolites, this process was disrupted because levels of H3K9me3 were globally elevated, preventing the spike in H3K9me3 at the DSB site that caused initial recruitment of TIP60 and MRE11 in normal cells. Further investigation revealed that the global increase in H3K9me3 in oncometabolite-high cells was caused by oncometabolite-mediated inhibition of the histone lysine demethylase KDM4B, an effect that could be mimicked by loss of KDM4B and rescued by expression of wild-type (but not catalytically inactive) KDM4B. Together, these results supply further evidence for the previously observed connection between insufficient DNA repair and metabolic abnormalities in cancer cells and provide a mechanistic explanation for this link.
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