Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair

Nature Genetics
Parker L SulkowskiPeter M Glazer

Abstract

The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively1-3. Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic.

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Citations

Feb 7, 2019·Histochemistry and Cell Biology·Thomas G PapathomasAxel Karl Walch
Feb 15, 2019·Genes·Cailin Wilson, Adam J Krieg
May 19, 2019·Cancers·Alberto CascónMercedes Robledo
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Dec 19, 2019·Antioxidants & Redox Signaling·Alessandra ScagliolaSimone Cardaci
Jun 25, 2020·International Journal of Molecular Sciences·Jean NakhleMarie-Luce Vignais
Jun 5, 2020·Nature·Parker L SulkowskiPeter M Glazer
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Methods Mentioned

BETA
ELISA
transfection
xenograft
xenografts
Assay
transfections
Protein
ELISAs
electrophoresis
Fluorescence

Software Mentioned

MultiQuant
Focinator
Stata
NIS Elements
Analyst
GraphPad Prism

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