Abstract
ATP-dependent chromatin remodeling complexes such as SWI/SNF (SWItch/Sucrose NonFermentable) have been implicated in DNA double-strand break (DSB) repair and damage responses. However, the regulatory mechanisms that control the function of chromatin remodelers in DNA damage response are largely unknown. Here, we show that ataxia telangiectasia mutated (ATM) mediates the phosphorylation of BRG1, the catalytic ATPase of the SWI/SNF complex that contributes to DSB repair by binding γ-H2AX-containing nucleosomes via interaction with acetylated histone H3 and stimulating γ-H2AX formation, at Ser-721 in response to DNA damage. ATM-mediated phosphorylation of BRG1 occurs rapidly and transiently after DNA damage. Phosphorylated BRG1 binds γ-H2AX-containing nucleosomes to form the repair foci. The Ser-721 phosphorylation of BRG1 is critical for binding γ-H2AX-containing nucleosomes and stimulating γ-H2AX formation and DSB repair. BRG1 binds to acetylated H3 peptides much better after phosphorylation at Ser-721 by DNA damage. However, the phosphorylation of Ser-721 does not significantly affect the ATPase and transcriptional activities of BRG1. These results, establishing BRG1 as a novel and functional ATM substrate, suggest that the ATM-mediated phosphorylation of BRG1 facilitates DSB repair by stimulating the association of this remodeler with γ-H2AX nucleosomes via enhancing the affinity to acetylated H3. Our work also suggests that the mechanism of BRG1 stimulation of DNA repair is independent of the remodeler’s enzymatic or transcriptional activities.
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Acknowledgements
We thank Rho H Seong (Seoul National University) for kindly providing the plasmids pREP4-p53RE-luc and flag-p53, and Seul-Ki Lee and Shin-Kyoung Hur for technical assistance. This work was supported by the National Research Foundation (NRF) grant funded by the Korea Ministry of Education and Science (MEST) (2012R1A2A2A01003744 to JK); the NRF grant funded by the MEST (2012R1A5A1048236); Ewha Global Top5 Grant 2013 and RP-Grant 2009 (to J-HP) funded by Ewha Womans University.
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Kwon, SJ., Park, JH., Park, EJ. et al. ATM-mediated phosphorylation of the chromatin remodeling enzyme BRG1 modulates DNA double-strand break repair. Oncogene 34, 303–313 (2015). https://doi.org/10.1038/onc.2013.556
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DOI: https://doi.org/10.1038/onc.2013.556
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