机构：[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.
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.
基金：
This
work was supported by National Cancer Institute grants 2R01CA109035 (Z.L.) and
1R0CA169603 (Z.L.), National Institute of Neurological Disorders and Stroke grant
1R01NS089754 (Z.L.), the MD Anderson Cancer Center Support Grant CA016672,
James S. McDonnell Foundation 21st Century Science Initiative in Brain Cancer
Research Award 220020318 (Z.L.), 2P50CA127001 (Brain Cancer SPORE), a Sister
Institution Network Fund from The University of Texas MD Anderson Cancer
Center (Z.L.), and the Odyssey Fellowship from MD Anderson (Y.J.). Z.L. is a
R. E. Rutherford Distinguished Professor
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2015]版：
大类|1 区生物
小类|1 区细胞生物学
最新[2023]版：
大类|1 区生物学
小类|1 区细胞生物学
第一作者：
第一作者机构：[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.
通讯作者：
通讯机构：[1]Brain Tumor Center and Department of Neuro-Oncology, 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.
推荐引用方式(GB/T 7714)：
Jiang Yuhui,Qian Xu,Shen Jianfeng,et al.Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation.[J].Nature cell biology.2015,17(9):1158-68.doi:10.1038/ncb3209.
APA：
Jiang Yuhui,Qian Xu,Shen Jianfeng,Wang Yugang,Li Xinjian...&Lu Zhimin.(2015).Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation..Nature cell biology,17,(9)
MLA：
Jiang Yuhui,et al."Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation.".Nature cell biology 17..9(2015):1158-68
生物