MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability

doi:10.1073/pnas.0601828103

MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability

Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030

Edited by Richard D. Kolodner, University of California at San Diego School of Medicine, La Jolla, CA, and approved June 20, 2006 (received for review March 6, 2006)

Abstract

Spindle assembly checkpoint (SAC) ensures bipolar attachment of chromosomes to the mitotic spindle and is essential for faithful chromosome segregation, thereby preventing chromosome instability (CIN). Genetic evidence suggests a causal link between compromised SAC, CIN, and cancer. Bloom syndrome (BS) is a genetic disorder that predisposes affected individuals to cancer. BS cells exhibit elevated rates of sister chromatid exchange, chromosome breaks, and CIN. The BS gene product, BLM, is a member of the RecQ helicases that are required for maintenance of genome stability. The BLM helicase interacts with proteins involved in DNA replication, recombination, and repair and is required for the repair of stalled-replication forks and in the DNA damage response. Here we present biochemical evidence to suggest a role of BLM phosphorylation during mitosis in maintaining chromosome stability. BLM is associated with the SAC kinase MPS1 and is phosphorylated at S144 in a MPS1-dependent manner. Phosphorylated BLM interacts with polo-like kinase 1, a mitotic kinase that binds to phospho-serine/threonine through its polo-box domain (PBD). Furthermore, BS cells expressing BLM-S144A show normal levels of sister chromatid exchange but fail to maintain the mitotic arrest when SAC is activated and exhibit a broad distribution of chromosome numbers. We propose that MPS1-dependent BLM phosphorylation is important for ensuring accurate chromosome segregation, and its deregulation may contribute to cancer.

Footnotes

^†To whom correspondence should be addressed. E-mail: yiw{at}bcm.tmc.edu
↵*Present address: Department of Microbiology, University of Washington, Box 358070, Seattle, WA 98195-8070.
Author contributions: M.L., J.Q., and Y.W. designed research; M.L., D.W.C., H.L., C.Z., J.Q., and Y.W. performed research; M.L., D.W.C., J.Q., and Y.W. analyzed data; and J.Q. and Y.W. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

BS,

Bloom syndrome;

PBD,

polo-box domain;

SAC,

spindle assembly checkpoint;

SCE,

sister chromatid exchange
Freely available online through the PNAS open access option.