Oncometabolites suppress DNA repair by disrupting local chromatin signalling

Parker L. Sulkowski, Sebastian Oeck, Jonathan Dow, Nicholas G. Economos, Lily Mirfakhraie, Yanfeng Liu, Katelyn Noronha, Xun Bao, Jing Li, Brian M. Shuch, Megan C. King, Ranjit S. Bindra () and Peter M. Glazer ()
Additional contact information
Parker L. Sulkowski: Yale University School of Medicine
Sebastian Oeck: Yale University School of Medicine
Jonathan Dow: Yale University School of Medicine
Nicholas G. Economos: Yale University School of Medicine
Lily Mirfakhraie: Yale University School of Medicine
Yanfeng Liu: Yale University School of Medicine
Katelyn Noronha: Yale University School of Medicine
Xun Bao: Wayne State University
Jing Li: Wayne State University
Brian M. Shuch: University of California at Los Angeles
Megan C. King: Yale University School of Medicine
Ranjit S. Bindra: Yale University School of Medicine
Peter M. Glazer: Yale University School of Medicine

Nature, 2020, vol. 582, issue 7813, 586-591

Abstract: Abstract Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer1. Increased levels of the metabolites 2-hydroxyglutarate, succinate and fumarate occur in human malignancies owing to somatic mutations in the isocitrate dehydrogenase-1 or -2 (IDH1 or IDH2) genes, or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), respectively2–4. Recent work has made an unexpected connection between these metabolites and DNA repair by showing that they suppress the pathway of homology-dependent repair (HDR)5,6 and confer an exquisite sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP) that are being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we determine the pathway by which these metabolites disrupt DNA repair. We show that oncometabolite-induced inhibition of the lysine demethylase KDM4B results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of HDR. Consequently, recruitment of TIP60 and ATM, two key proximal HDR factors, is substantially impaired at DNA breaks, with reduced end resection and diminished recruitment of downstream repair factors. These findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.

Date: 2020
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DOI: 10.1038/s41586-020-2363-0

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