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

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 ionizing radiation (IR) induces DNA-PK-dependent phosphorylation of nuclear fumarase at T236, which leads to an in...

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Autores principales: Jiang, Yuhui, Qian, Xu, Shen, Jianfeng, Wang, Yugang, Li, Xinjian, Liu, Rui, Xia, Yan, Chen, Qianming, Peng, Guang, Lin, Shiaw-Yih, Lu, Zhimin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800990/
https://www.ncbi.nlm.nih.gov/pubmed/26237645
http://dx.doi.org/10.1038/ncb3209
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author Jiang, Yuhui
Qian, Xu
Shen, Jianfeng
Wang, Yugang
Li, Xinjian
Liu, Rui
Xia, Yan
Chen, Qianming
Peng, Guang
Lin, Shiaw-Yih
Lu, Zhimin
author_facet Jiang, Yuhui
Qian, Xu
Shen, Jianfeng
Wang, Yugang
Li, Xinjian
Liu, Rui
Xia, Yan
Chen, Qianming
Peng, Guang
Lin, Shiaw-Yih
Lu, Zhimin
author_sort Jiang, Yuhui
collection PubMed
description 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 ionizing radiation (IR) induces DNA-PK-dependent phosphorylation of nuclear fumarase at T236, 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 K36; in turn, this increases the accumulation of the Ku70-containing DNA-PK at DSB regions for non-homologous end joining (NHEJ) 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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spelling pubmed-48009902016-03-21 Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation Jiang, Yuhui Qian, Xu Shen, Jianfeng Wang, Yugang Li, Xinjian Liu, Rui Xia, Yan Chen, Qianming Peng, Guang Lin, Shiaw-Yih Lu, Zhimin Nat Cell Biol Article 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 ionizing radiation (IR) induces DNA-PK-dependent phosphorylation of nuclear fumarase at T236, 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 K36; in turn, this increases the accumulation of the Ku70-containing DNA-PK at DSB regions for non-homologous end joining (NHEJ) 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. 2015-08-03 2015-09 /pmc/articles/PMC4800990/ /pubmed/26237645 http://dx.doi.org/10.1038/ncb3209 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Jiang, Yuhui
Qian, Xu
Shen, Jianfeng
Wang, Yugang
Li, Xinjian
Liu, Rui
Xia, Yan
Chen, Qianming
Peng, Guang
Lin, Shiaw-Yih
Lu, Zhimin
Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
title Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
title_full Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
title_fullStr Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
title_full_unstemmed Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
title_short Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
title_sort local generation of fumarate promotes dna repair through inhibition of histone h3 demethylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800990/
https://www.ncbi.nlm.nih.gov/pubmed/26237645
http://dx.doi.org/10.1038/ncb3209
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