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B.S. 2005 Nanjing University
Thesis Advisor: Nancy C. Walworth, PhD
Graduate Program in Cellular and Molecular Pharmacology
Pharmacology Department Conference Room
4th floor, RWJMS
Tuesday, June 22, 2010
Checkpoint pathways play important roles in regulating cell cycle progression in response to DNA damage. The fission yeast msc1 gene was identified as a multi-copy suppressor of the chk1 mutant which is defective in the DNA damage checkpoint pathway. Msc1, which contains three plant homeodomain (PHD) finger motifs and one jumonji C (jmjC) domain, is required for chromosome stability. The work of the thesis identified that Msc1 is a component of the Swr1 complex. Others have shown that the Swr1 complex facilitates deposition of the histone variant H2A.Z into chromatin.
Previous studies in our lab showed that Msc1 acts through H2A.Z to promote survival of cells in which the DNA damage checkpoint is compromised. In this study, the cells lacking Msc1 and Swr1 show similar phenotypes, indicating that they act in the same
pathway. The C-terminal PHD fingers of Msc1 are responsible for binding to Swr1 and necessary for the function of Msc1. However, the association of Msc1 and Swr1 is not sufficient for Msc1 function, and the activity of Msc1 based on a cysteine residue within the Zn++-binding domain of PHD2 is critical for function. PHD fingers of Msc1 were found to have ubiquitin E3 ligase activity and mutations of cysteine residues within these domains abolish ligase activity. We speculate that the ability of Msc1 to facilitate ubiquitin transfer is critical for the function it mediates through its association with Swr1.
The centromere is crucial for maintaining chromosome stability and previous studies in our lab showed that loading of the histione H3 variant Cnp1 at the centomere is decreased when Msc1 is absent. Cnp1 loading at the centromere is also
reduced when Swr1 is absent. Furthermore, the expression pattern of a reporter gene ura4 which is inserted at the centromere is changed in the msc1 and swr1 deletion strains. I have also shown direct presence of Msc1 and Swr1 at the centromere.
Cohesin recruitment at the centromere is slightly reduced in the msc1 and swr1 deletion strains. Altogether, these results suggest that Msc1 and Swr1 contribute to centromere function and genome stability in fission yeast.