Back to Search
Start Over
Oncometabolites suppress DNA repair by disrupting local chromatin signaling
- Source :
- Nature
- Publication Year :
- 2020
-
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.
- Subjects :
- 0301 basic medicine
Jumonji Domain-Containing Histone Demethylases
DNA Repair
SDHB
DNA repair
Poly ADP ribose polymerase
Medizin
SDHA
Ataxia Telangiectasia Mutated Proteins
Poly(ADP-ribose) Polymerase Inhibitors
Methylation
Lysine Acetyltransferase 5
Article
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Neoplasms
Humans
Homologous Recombination
Multidisciplinary
biology
DNA Breaks
Chromatin
Cell biology
030104 developmental biology
Histone
030220 oncology & carcinogenesis
biology.protein
Demethylase
SDHD
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14764687 and 00280836
- Volume :
- 582
- Issue :
- 7813
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....930f51da546111372a445e8362ccb2f1