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

Yuhui Jiang; Xu Qian; Jianfeng Shen; Yugang Wang; Xinjian Li; Rui Liu; Yan Xia; Qianming Chen; Guang Peng; Shiaw Yih Lin; Zhimin Lu

doi:10.1038/ncb3209

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

Yuhui Jiang, Xu Qian, Jianfeng Shen, Yugang Wang, Xinjian Li, Rui Liu, Yan Xia, Qianming Chen, Guang Peng, Shiaw Yih Lin, Zhimin Lu

Research output: Contribution to journal › Article › peer-review

141 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1158-1168
Number of pages	11
Journal	Nature cell biology
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/ncb3209
State	Published - Sep 1 2015

ASJC Scopus subject areas

Cell Biology

MD Anderson CCSG core facilities

Functional Genomics Core

Access to Document

10.1038/ncb3209

Cite this

@article{0caed911e9c242ed91a44f9837eab4ee,

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.",

author = "Yuhui Jiang and Xu Qian and Jianfeng Shen and Yugang Wang and Xinjian Li and Rui Liu and Yan Xia and Qianming Chen and Guang Peng and Lin, {Shiaw Yih} and Zhimin Lu",

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = sep,

day = "1",

doi = "10.1038/ncb3209",

language = "English (US)",

volume = "17",

pages = "1158--1168",

journal = "Nature cell biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation

AU - Jiang, Yuhui

AU - Qian, Xu

AU - Shen, Jianfeng

AU - Wang, Yugang

AU - Li, Xinjian

AU - Liu, Rui

AU - Xia, Yan

AU - Chen, Qianming

AU - Peng, Guang

AU - Lin, Shiaw Yih

AU - Lu, Zhimin

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84940478601&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940478601&partnerID=8YFLogxK

U2 - 10.1038/ncb3209

DO - 10.1038/ncb3209

M3 - Article

C2 - 26237645

AN - SCOPUS:84940478601

SN - 1465-7392

VL - 17

SP - 1158

EP - 1168

JO - Nature cell biology

JF - Nature cell biology

IS - 9

ER -

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this