title: Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation.
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.
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The Institute of Cell Metabolism, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Shen
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Li
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
authors.forename: Qianming
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Shiaw-Yih
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism; D005649:Fumarate Hydratase / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008745:Methylation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: D044783:F-Box Proteins; D005650:Fumarates; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D051747:DNA-Activated Protein Kinase; D005649:Fumarate Hydratase