Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair
Open accessAbstract
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, respectively 1-3. 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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High levels of succinate and fumarate in SDH- and FH-deficient cancers impair homologous recombination DNA repair by inhibiting α-ketoglutarate-dependent enzymes including KDM4A and KDM4B.
“In addition to their roles in the TCA cycle, high levels of succinate and fumarate in SDH- and FH-deficient cancers impair homologous recombination DNA repair (109). This repair pathway requires the α-ketoglutarate-dependent histone demethylases KDM4A and KDM4B. Like D-2HG, succinate and fumarate, at high concentrations, inhibit α-ketoglutarate-dependent enzymes, including KDM4A and KDM4B.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [109]
Somatic mutations in IDH1 and IDH2 are among the first genetic events in tumorigenesis in human glioma and AML and initiate pathogenesis by a common mechanism.
“Genomic studies have established that somatic mutations in IDH1 and IDH2 are perhaps the first genetic events to occur during tumorigenesis in human glioma and AML, and appear to initiate pathogenesis by a common mechanism103,115-117.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [117]
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References 21 · Cited by 213
- Authors
- Sulkowski, P. L., Sundaram, R. K., Oeck, S., Corso, C. D., Liu, Y., Noorbakhsh, S., Niger, M., Boeke, M., Ueno, D., Kalathil, A. N., Bao, X., Li, J., Shuch, B., Bindra, R. S., & Glazer, P. M.
- Affiliations
- Yale University (US)
- Wayne State University (US)
- Corresponding author
- Shuch, Brian
- Bindra, Ranjit S.
- Glazer, Peter M.
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-07-16
- Volume
- 50
- Issue
- 8
- Pages
- 1086-1092
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6072579
- OpenAlex
- W2884857090
- Cited by
- 213
- References
- 21
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 25 · 2023: 24 · 2022: 41 · 2021: 31 · 2020: 33 · 2019: 22 · 2018: 2
- FWCI
- 8.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (F31CA260794, R01CA215453, R01CA168733, R35CA197574)
- National Institute of General Medical Sciences (T32GM007223)
- National Institute of Environmental Health Sciences (R01ES005775)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007149)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- hereditary cancer, fumarate hydratase, succinate dehydrogenase, hereditary leiomyomatosis and renal cell carcinoma, fumarate, succinic acid, synthetic lethality, PARP inhibitors, DNA double-strand break repair, cancer susceptibility
- MeSH terms
- Adrenal Gland Neoplasms, Cell Line, Citric Acid Cycle, Fumarates, Humans, Neoplastic Syndromes, Hereditary, Pheochromocytoma, Skin Neoplasms, Uterine Neoplasms, Germ-Line Mutation, Leiomyomatosis, Succinic Acid, Cell Line, Tumor, DNA Breaks, Double-Stranded, HEK293 Cells, Recombinational DNA Repair
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