Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl

Jiang, Z and Kamath, R and Jin, S and Balasubramani, M and Pandita, TK and Rajasekaran, B (2011) Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl. Molecular Cancer, 10.

Published Version
Available under License : See the attached license file.

Download (3MB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)


Background: The 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.Results: We 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 (KXXK--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.Conclusion: Collective 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. © 2011 Jiang et al; licensee BioMed Central Ltd.


Social Networking:
Share |


Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Jiang, Z
Kamath, R
Jin, S
Balasubramani, M
Pandita, TK
Rajasekaran, B
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 22 July 2011
Date Type: Publication
Journal or Publication Title: Molecular Cancer
Volume: 10
DOI or Unique Handle: 10.1186/1476-4598-10-88
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
Date Deposited: 31 Oct 2016 16:30
Last Modified: 04 Feb 2019 15:59


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item