QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 8, 3212-3220, August 2008

This Article Full Text Full Text (PDF) All Versions of this Article: E07-11-1171v1 19/8/3212    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Jamil, S. Articles by Duronio, V. PubMed PubMed Citation Articles by Jamil, S. Articles by Duronio, V.

An Essential Role for MCL-1 in ATR-mediated CHK1 Phosphorylation

Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC, V6H 3Z6 Canada

Submitted November 26, 2007; Revised April 16, 2008; Accepted May 8, 2008
Monitoring Editor: William P. Tansey

Here we report a novel role for myeloid cell leukemia 1 (Mcl-1), a Bcl-2 family member, in regulating phosphorylation and activation of DNA damage checkpoint kinase, Chk1. Increased expression of nuclear Mcl-1 and/or a previously reported short nuclear form of Mcl-1, snMcl-1, was observed in response to treatment with low concentrations of etoposide or low doses of UV irradiation. We showed that after etoposide treatment, Mcl-1 could coimmunoprecipitate with the regulatory kinase, Chk1. Chk1 is a known regulator of DNA damage response, and its phosphorylation is associated with activation of the kinase. Transient transfection with Mcl-1 resulted in an increase in the expression of phospho-Ser345 Chk1, in the absence of any evidence of DNA damage, and accumulation of cells in G2. Importantly, knockdown of Mcl-1 expression abolished Chk1 phosphorylation in response to DNA damage. Mcl-1 could induce Chk1 phosphorylation in ATM-negative (ataxia telangectasia mutated) cells, but this response was lost in ATR (AT mutated and Rad3 related)-defective cells. Low levels of UV treatment also caused transient increases in Mcl-1 levels and an ATR-dependent phosphorylation of Chk1. Together, our results strongly support an essential regulatory role for Mcl-1, perhaps acting as an adaptor protein, in controlling the ATR-mediated regulation of Chk1 phosphorylation.

Address correspondence to: Vincent Duronio (vduronio{at}interchange.ubc.ca)

Abbreviations used: ATM, ataxia telangectasia mutated; ATR, AT mutated and Rad3 related; BH, Bcl-2 homology; Chk1, checkpoint kinase 1; Mcl-1, myeloid cell leukemia-1.