Abstract
Xbp1 has been shown to regulate the cell cycle as a transcriptional repressor in budding yeast Saccharomyces cerevisiae. In this study, we demonstrated that Xbp1 regulates DNA double-strand break (DSB) repair in S. cerevisiae. Xbp1 physically and genetically interacts with the histone deacetylase Rpd3 complex. Chromatin immunoprecipitation revealed that Xbp1 is required for efficient deacetylation of histone H4 flanking DSBs by the Rpd3 complex. Deletion of XBP1 leads to the delayed deacetylation of histone H4, which is coupled with increased nucleosome displacement, increased DNA end resection and decreased non-homologous end-joining (NHEJ). In response to DNA damage, Xbp1 is upregulated in a Mec1-Rad9-Rad53 checkpoint pathway-dependent manner and undergoes dephosphorylation. Cdk1, a central regulator of S. cerevisiae cell cycle, is responsible for Xbp1 phosphorylation at residues Ser146, Ser271 and Ser551. Substitution of these serine residues with alanine not only increases the association of Xbp1 with the Rpd3 complex and its recruitment to a DSB, but also promotes DSB repair. Together, our findings reveal a role for Xbp1 in DSB repair via NHEJ through regulation of histone H4 acetylation and nucleosome displacement in a positive feedback manner.
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Acknowledgements
We are grateful to Dr James E Haber (Brandeis University, USA) for yeast strains, insightful suggestions and critical comments on the manuscript, Drs Aaron D Gitler (University of Pennsylvania School of Medicine, USA), Raymond J Deshaies (California Institute of Technology, USA) and Stephen P Jackson (University of Cambridge, UK) for yeast strains, Dr Jürg Bähler (Wellcome Trust Sanger Institute, UK) for plasmids, Drs Jin-Qiu Zhou (Institute of Biochemistry and Cell Biology, SIBS, CAS, China) and Jijie Chai (National Institute of Biological Sciences, China) for technical support, and Dr Haiying Hang (Institute of Biophysics, CAS, China) for technical advice. We also thank Ting Martin Ma for critical reading and Junjie Luo for statistical analysis. This work was supported by grants from the National Natural Science Foundation of China (30930050, 30921004) and 973 Program (2006CB943401, 2006CB910102, 2010CB833703, 2010CB833706).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
Xbp1 could not affect global acetylation level of histone H3 or H4. (PDF 136 kb)
Supplementary information, Figure S2
The Rpd3 complex promotes the recruitment of Xbp1 to DSB. (PDF 155 kb)
Supplementary information, Figure S3
3SA mutation enhances the binding of Xbp1 to DSBs. (PDF 116 kb)
Supplementary information, Figure S4
Xbp1 cannot bind to regions 0.4 kb or 1.6 kb away upstream of the HO cut site at the MAT locus without HO induction. (PDF 113 kb)
Supplementary information, Table S1
Yeast strains used in this study. (PDF 89 kb)
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Tao, R., Chen, H., Gao, C. et al. Xbp1-mediated histone H4 deacetylation contributes to DNA double-strand break repair in yeast. Cell Res 21, 1619–1633 (2011). https://doi.org/10.1038/cr.2011.58
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DOI: https://doi.org/10.1038/cr.2011.58
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