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Originally published as Genetics Published Articles Ahead of Print on October 18, 2007.

Genetics, Vol. 177, 1487-1497, November 2007, Copyright © 2007
doi:10.1534/genetics.107.078691

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Msc1 Acts Through Histone H2A.Z to Promote Chromosome Stability in Schizosaccharomyces pombe

Shakil Ahmed1,2, Barbara Dul1, Xinxing Qiu and Nancy C. Walworth3

Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Joint Graduate Program in Cellular and Molecular Pharmacology, UMDNJ-Graduate School of Biomedical Sciences and Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-5635

3 Corresponding author: Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635.
E-mail: walworna{at}umdnj.edu

As a central component of the DNA damage checkpoint pathway, the conserved protein kinase Chk1 mediates cell cycle progression when DNA damage is generated. Msc1 was identified as a multicopy suppressor capable of facilitating survival in response to DNA damage of cells mutant for chk1. We demonstrate that loss of msc1 function results in an increased rate of chromosome loss and that an msc1 null allele exhibits genetic interactions with mutants in key kinetochore components. Multicopy expression of msc1 robustly suppresses a temperature-sensitive mutant (cnp1-1) in the centromere-specific histone H3 variant CENP-A, and localization of CENP-A to the centromere is compromised in msc1 null cells. We present several lines of evidence to suggest that Msc1 carries out its function through the histone H2A variant H2A.Z, encoded by pht1 in fission yeast. Like an msc1 mutant, a pht1 mutant also exhibits chromosome instability and genetic interactions with kinetochore mutants. Suppression of cnp1-1 by multicopy msc1 requires pht1. Likewise, suppression of the DNA damage sensitivity of a chk1 mutant by multicopy msc1 also requires pht1. We present the first genetic evidence that histone H2A.Z may participate in centromere function in fission yeast and propose that Msc1 acts through H2A.Z to promote chromosome stability and cell survival following DNA damage.




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E. B. Gomez, R. L. Nugent, S. Laria, and S. L. Forsburg
Schizosaccharomyces pombe Histone Acetyltransferase Mst1 (KAT5) Is an Essential Protein Required for Damage Response and Chromosome Segregation
Genetics, June 1, 2008; 179(2): 757 - 771.
[Abstract] [Full Text] [PDF]


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