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Critical role of monoubiquitination of histone H2AX protein in histone H2AX phosphorylation and DNA damage response.


ABSTRACT: DNA damage response is an important surveillance mechanism used to maintain the integrity of the human genome in response to genotoxic stress. Histone variant H2AX is a critical sensor that undergoes phosphorylation at serine 139 upon genotoxic stress, which provides a docking site to recruit the mediator of DNA damage checkpoint protein 1 (MDC1) and DNA repair protein complex to sites of DNA breaks for DNA repair. Here, we show that monoubiquitination of H2AX is induced upon DNA double strand breaks and plays a critical role in H2AX Ser-139 phosphorylation (?-H2AX), in turn facilitating the recruitment of MDC1 to DNA damage foci. Mechanistically, we show that monoubiquitination of H2AX induced by RING finger protein 2 (RNF2) is required for the recruitment of active ataxia telangiectasia mutated to DNA damage foci, thus affecting the formation of ?-H2AX. Importantly, a defect in monoubiquitination of H2AX profoundly enhances ionizing radiation sensitivity. Our study therefore suggests that monoubiquitination of H2AX is an important step for DNA damage response and may have important clinical implications for the treatment of cancers.

SUBMITTER: Wu CY 

PROVIDER: S-EPMC3162441 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Critical role of monoubiquitination of histone H2AX protein in histone H2AX phosphorylation and DNA damage response.

Wu Ching-Yuan CY   Kang Hong-Yo HY   Yang Wei-Lei WL   Wu Juan J   Jeong Yun Seong YS   Wang Jing J   Chan Chia-Hsin CH   Lee Szu-Wei SW   Zhang Xian X   Lamothe Betty B   Campos Alejandro D AD   Darnay Bryant G BG   Lin Hui-Kuan HK  

The Journal of biological chemistry 20110620 35


DNA damage response is an important surveillance mechanism used to maintain the integrity of the human genome in response to genotoxic stress. Histone variant H2AX is a critical sensor that undergoes phosphorylation at serine 139 upon genotoxic stress, which provides a docking site to recruit the mediator of DNA damage checkpoint protein 1 (MDC1) and DNA repair protein complex to sites of DNA breaks for DNA repair. Here, we show that monoubiquitination of H2AX is induced upon DNA double strand b  ...[more]

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