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

Nat Genet. 2018 Aug;50(8):1086-1092. doi: 10.1038/s41588-018-0170-4. Epub 2018 Jul 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / genetics
  • Cell Line
  • Cell Line, Tumor
  • Citric Acid Cycle / drug effects
  • Citric Acid Cycle / genetics*
  • DNA Breaks, Double-Stranded
  • Fumarates / pharmacology
  • Germ-Line Mutation
  • HEK293 Cells
  • Humans
  • Leiomyomatosis / genetics
  • Neoplastic Syndromes, Hereditary / genetics*
  • Pheochromocytoma / genetics
  • Recombinational DNA Repair*
  • Skin Neoplasms / genetics
  • Succinic Acid / pharmacology
  • Uterine Neoplasms / genetics


  • Fumarates
  • Succinic Acid

Supplementary concepts

  • Hereditary leiomyomatosis and renal cell cancer