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

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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.