Characterization of KAP1 acetylation and its roles in DNA damage repair

Abstract

KAP1, also known as TRIM28, is a heterochromatin-associated protein. It mainly functions in formation of heterochromatin, transcriptional silencing and maintenance of genome integrity. KAP1 also participates in DNA damage repair. In particular, the phosphorylation of KAP1 at pS824 and pS473 is important for its dissociation from the heterochromatin and chromatin relaxation upon DNA damage. However, the biological relevance of other post-translational modifications of KAP1 and how they crosstalk with its phosphorylation remain unknown. Recently, we discovered that KAP1 is a substrate of SIRT6. It can be deacetylated by SIRT6 in vitro. Comparison of wildtype and SIRT6 knockout immortalized MEF also indicates that acetylation of KAP1 is significantly increased when SIRT6 is depleted. We further found that KAP1 can be acetylated by histone acetyltransferases such as MOF, p300, GCN5 and Tip60. The overall acetylation levels of KAP1 will be decreased in response to irradiation-induced DNA damage, suggesting that acetylation of KAP1 plays certain roles in the regulation of DNA damage. This also parallels to our finding that SIRT6 may affect the dissociation of KAP1 from heterochromatin in response to DNA damage repair. Reference 1. Sushma Iyengar and Peggy J. Farnham (2011) JBC 286: 26267-26276 2. Nathaly Castro-Diaz, Gabriela Ecco, Andrea Coluccio, Adamandia Kapopoulou, Benyamin Yazdanpanah, Marc Friedli, Julien Duc, Suk Min Jang, Priscilla Turelli, and Didier Trono (2014) Gene & Development 28:1397–1409 3. Yael Ziv, Dana Bielopolski, Yaron Galanty, Claudia Lukas, Yoichi Taya, David C. Schultz, Jiri Lukas, Simon Bekker-Jensen, Jiri Bartek and Yosef Shiloh (2006) Nature Cell Biol 8:870-876 4. Aaron A. Goodarzi, Angela T. Noon, Dorothee Deckbar, Yael Ziv, Yosef Shiloh, Markus Lo ̈ brich, and Penny A. Jeggo (2008) Mol Cell 31:167-177