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BRCA1 function in the intra-S checkpoint is activated by acetylation via a pCAF/SIRT1 axis

Oncogene volume 37, pages 2343–2350 (2018)Cite this article

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Abstract

Breast cancer associated gene 1 (BRCA1) function has been shown to be regulated by phosphorylation but the role of acetylation has not been determined. Therefore, we tested whether BRCA1 can be acetylated by the acetyltransferases P300/CBP-associated factor (pCAF), GCN5, and p300. p300 exhibited the highest level of BRCA1 acetylation; however, there was also a decrease in the total level of BRCA1. Therefore, we focused on pCAF and GCN5 because they both acetylated BRCA1 without affecting BRCA1 expression. Further analysis indicated that the acetylated form of BRCA1 is deacetylated by wild-type (WT) SIRT1, but not deacetylase mutant SIRT1, suggesting that SIRT1 is a specific deacetylase of BRCA1. We demonstrated that lysine 830 of BRCA1 is a preferential acetylation site by pCAF and tested its function in embryonic stem (ES) cells by changing lysine 830 to arginine using a transcription activator-like effector nuclease (TALEN) system. After exposure to DNA damage-inducing UV radiation, the viability of BRCA1 K830R mutant cells is greater than the WT ES cells. Further analysis using additional cell lines indicated that the BRCA1 K830R mutation impairs the intra-S checkpoint. Also, checkpoint kinase 1 (CHK1) phosphorylation was less in K830R cells as compared with WT cells after UV exposure. These data suggest that acetylation of BRCA1 on lysine 830 activates BRCA1 function at the intra-S checkpoint after DNA damage.

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Acknowledgements

We thank Dr. Zhen Xiao for BRCA1 acetylation analysis and the members of the Deng laboratory for helpful discussion. This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA, and by the Chair Professor Grant (CPG2017-00026-FHS), granted to C.D. by University of Macau, Macau SAR, China; Macao Science and Technology Development Fund grants (065/2015/A2 and 094/2015/A3), granted to C.D.

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    Authors and Affiliations

    1. Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

      Tyler J. Lahusen, Seung-Jin Kim & Chu-Xia Deng

    2. Faculty of Health Sciences, University of Macau, Macau, SAR, China

      Kai Miao, Zebin Huang, Xiaoling Xu & Chu-Xia Deng

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    1. Tyler J. Lahusen
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    Correspondence to Chu-Xia Deng.

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    Tyler J. Lahusen and Seung-Jin Kim contributed equally to this work.

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    Lahusen, T.J., Kim, SJ., Miao, K. et al. BRCA1 function in the intra-S checkpoint is activated by acetylation via a pCAF/SIRT1 axis. Oncogene 37, 2343–2350 (2018). https://doi.org/10.1038/s41388-018-0127-1

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