Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl

Molecular Cancer

Research

Zhihua Jiang¹  Ravindra Kamath¹  Baskaran Rajasekaran²  Tej K Pandita³  Manimalha Balasubramani⁴  Shunquian Jin⁵ 

[1] Department of Microbiology and Molecular Genetics (Z.J., R.V., R.B), University Drive Pittsburgh, 15261, 15240, Pittsburgh, PA, USA;Department of Microbiology and Molecular Genetics (Z.J., R.V., R.B), University Drive Pittsburgh, 15261, 15240, Pittsburgh, PA, USA;Pittsburgh Cancer Institute, 15261, Pittsburgh, PA, USA;Department of Radiation Oncology, UT SouthWestern Medical Center, 75390, Dallas, TX, USA;Genomics and Proteomics Core Laboratories, 3343 Forbes Avenue, 15260, Pittsburgh, PA, USA;Veterans Affairs Health Care, University Drive Pittsburgh, 15261, 15240, Pittsburgh, PA, USA;

关键词: DNA damage response;    histone acetyl-transferase;    c-Abl tyrosine kinase;    Apoptosis;   

DOI  :  10.1186/1476-4598-10-88

 received in 2010-11-12, accepted in 2011-07-22,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundThe proto-oncogene, c-Abl encodes a ubiquitously expressed tyrosine kinase that critically governs the cell death response induced by genotoxic agents such as ionizing radiation and cisplatin. The catalytic function of Abl, which is essential for executing DNA damage response (DDR), is normally tightly regulated but upregulated several folds upon IR exposure due to ATM-mediated phosphorylation on S465. However, the mechanism/s leading to activation of Abl's apoptotic activity is currently unknown.ResultsWe investigated the role of acetyl modification in regulating apoptotic activity of Abl and the results showed that DNA strand break-inducing agents, ionizing radiation and bleomycin induced Abl acetylation. Using mass spectrophotometry and site-specific acetyl antibody, we identified Abl K921, located in the DNA binding domain, and conforming to one of the lysine residue in the consensus acetylation motif (K XXK--X3-5--SGS) is acetylated following DNA damage. We further observed that the S465 phosphorylated Abl is acetyl modified during DNA damage. Signifying the modification, cells expressing the non acetylatable K921R mutant displayed attenuated apoptosis compared to wild-type in response to IR or bleomycin treatment. WT-Abl induced apoptosis irrespective of new protein synthesis. Furthermore, upon γ-irradiation K921R-Abl displayed reduced chromatin binding compared to wild type. Finally, loss of Abl K921 acetylation in Tip60-knocked down cells and co-precipitation of Abl with Tip60 in DNA damaged cells identified Tip60 as an Abl acetylase.ConclusionCollective data showed that DNA damage-induced K921 Abl acetylation, mediated by Tip60, stimulates transcriptional-independent apoptotic activity and chromatin-associative property thereby defining a new regulatory mechanism governing Abl's DDR function.

【 授权许可】

Unknown   
© Jiang et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.