Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
Open accessAbstract
Histone methylation regulates DNA repair. However, the mechanisms that underlie the regulation of histone methylation during this repair remain to be further defined. Here, we show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. Locally generated fumarate inhibits KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 Lys 36; in turn, this increases the accumulation of the Ku70-containing DNA-PK at DSB regions for non-homologous end-joining DNA repair and cell survival. These findings reveal a feedback mechanism that underlies DNA-PK regulation by chromatin-associated fumarase and an instrumental function of fumarase in regulating histone H3 methylation and DNA repair.
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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 [116]
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References 32 · Cited by 208
- Authors
- Jiang, Y., Qian, X., Shen, J., Wang, Y., Li, X., Liu, R., Xia, Y., Chen, Q., Peng, G., Lin, S.-Y., & Lu, Z.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Sichuan University (CN)
- Corresponding author
- Lu, Zhimin
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2015-08-03
- Volume
- 17
- Issue
- 9
- Pages
- 1158-1168
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4800990
- OpenAlex
- W1094391616
- Cited by
- 208
- References
- 32
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 19 · 2023: 16 · 2022: 20 · 2021: 28 · 2020: 19 · 2019: 20 · 2018: 20 · 2017: 14 · 2016: 12 · 2015: 4
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-04-09)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (F31CA260794, CA 016672, R01CA109035, 1R0 CA169603, R01CA169603, P30CA016672, P50CA127001)
- National Institute of Neurological Disorders and Stroke (R01NS089754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- fumarase, fumarate, KDM2B, DNA-dependent protein kinase, ionizing radiation, DNA double-strand breaks, non-homologous end joining, Ku70, H2A.Z, histone methylation, DNA repair, chromatin
- MeSH terms
- Amino Acid Sequence, Cell Survival, DNA Repair, Fumarate Hydratase, Fumarates, HeLa Cells, Histones, Humans, Methylation, Molecular Sequence Data, Protein Binding, Protein Processing, Post-Translational, Protein Transport, F-Box Proteins, DNA-Activated Protein Kinase, DNA Breaks, Double-Stranded, Jumonji Domain-Containing Histone Demethylases
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