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      Oncometabolites suppress DNA repair by disrupting local chromatin signaling

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer 1. Elevated levels of the metabolites, 2-hydroxyglutarate (2HG), succinate, and fumarate, occur in human malignancies due to somatic mutations in the isocitrate dehydrogenase-1/2 (IDH1/2) genes or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes, respectively 24 . 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 poly (ADP-ribose) polymerase (PARP) inhibitors that is being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we elucidate 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 significantly 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.

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          Most cited references 29

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            XRCC3 promotes homology-directed repair of DNA damage in mammalian cells.

            Homology-directed repair of DNA damage has recently emerged as a major mechanism for the maintenance of genomic integrity in mammalian cells. The highly conserved strand transferase, Rad51, is expected to be critical for this process. XRCC3 possesses a limited sequence similarity to Rad51 and interacts with it. Using a novel fluorescence-based assay, we demonstrate here that error-free homology-directed repair of DNA double-strand breaks is decreased 25-fold in an XRCC3-deficient hamster cell line and can be restored to wild-type levels through XRCC3 expression. These results establish that XRCC3-mediated homologous recombination can reverse DNA damage that would otherwise be mutagenic or lethal.
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              Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases.

              Histone methylation regulates chromatin structure, transcription, and epigenetic state of the cell. Histone methylation is dynamically regulated by histone methylases and demethylases such as LSD1 and JHDM1, which mediate demethylation of di- and monomethylated histones. It has been unclear whether demethylases exist that reverse lysine trimethylation. We show the JmjC domain-containing protein JMJD2A reversed trimethylated H3-K9/K36 to di- but not mono- or unmethylated products. Overexpression of JMJD2A but not a catalytically inactive mutant reduced H3-K9/K36 trimethylation levels in cultured cells. In contrast, RNAi depletion of the C. elegans JMJD2A homolog resulted in an increase in general H3-K9Me3 and localized H3-K36Me3 levels on meiotic chromosomes and triggered p53-dependent germline apoptosis. Additionally, other human JMJD2 subfamily members also functioned as trimethylation-specific demethylases, converting H3-K9Me3 to H3-K9Me2 and H3-K9Me1, respectively. Our finding that this family of demethylases generates different methylated states at the same lysine residue provides a mechanism for fine-tuning histone methylation.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                29 April 2020
                03 June 2020
                June 2020
                03 December 2020
                : 582
                : 7813
                : 586-591
                Affiliations
                [1 ]Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520
                [2 ]Department of Genetics, Yale University School of Medicine, New Haven, CT 06520
                [3 ]Department of Medical Oncology, University of Duisburg-Essen, Essen, Germany
                [4 ]Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
                [5 ]Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520
                [6 ]Karmanos Cancer Institute, Wayne State University, Detroit MI 48201
                [7 ]Department of Urology, University of California at Los Angeles, Los Angeles, CA 90095
                [8 ]Department of Pathology, Yale University School of Medicine, New Haven, CT 06520
                Author notes

                Author contributions. P.L.S. designed and performed experiments and contributed to all aspects of the study. S.O. designed experiments and performed and analyzed imaging studies and laser micro-stripe irradiation. J.D. and N.E. performed DNA repair and cell biology assays and contributed to data analysis and compiling of the manuscript. Y.L. designed and performed the tumor growth delay assays. B.S., X.B., and K.N. provided reagents and contributed to the experiments. L.M. and M.C.K. designed and performed end resection assays. J.L. performed LC/MS assays. P.M.G. and R.S.B. conceptualized and supervised the study and interpreted the data. P.M.G., R.S.B., M.C.K., and P.L.S. wrote the manuscript.

                [* ]These authors jointly directed this work. Correspondence should be addressed to: Peter M. Glazer ( peter.glazer@ 123456yale.edu ), Ranjit S. Bindra ( ranjit.bindra@ 123456yale.edu ).
                Article
                NIHMS1589129
                10.1038/s41586-020-2363-0
                7319896
                32494005

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