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Nat Cell Biol. 2015 Sep;17(9):1158-68. doi: 10.1038/ncb3209. Epub 2015 Aug 3.

Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation.

Author information

1
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2
The Institute of Cell Metabolism, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
3
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
4
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
5
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
6
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7
The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.

Abstract

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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PMID:
26237645
PMCID:
PMC4800990
DOI:
10.1038/ncb3209
[Indexed for MEDLINE]
Free PMC Article

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