PDS5P IN SISTER CHROMATID COHESION

Carnegie Institution Of Washington, D.C., Washington DC

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Abstract

DESCRIPTION (verbatim from the applicant's abstract): DNA is duplicated and packaged to ensure that a complete genome is transmitted to each daughter cell. Two types of packaging, sister chromatid cohesion and condensation are essential for proper chromosome segregation. Budding yeast proteins Pds5p and Mcdlp are essential for both cohesion and condensation. Our long-term goal is use Pds5p and Mcdlp as tools to elucidate the molecular mechanism responsible for sister chromatid cohesion and to examine the role that cohesion plays in condensation and the maintenance of genetic stability. These studies will investigate how Pds5p and Mcd1p bind to chromosomes and to other chromosomal proteins to create functional mitotic chromosome& PCR will be use to identify the specific DNA sequences that specify where the sites of cohesion axe formed and how there are regulated. Fluorescence in situ hybridization (FISH) will be used to examine the nature of the connection between cohesion and condensation by assessing how mutants in cohesion distort chromosome structure. The types of genetic instability generated by mutations in pds5 and mcd1 will be quantified by measuring unequal sister chromatid recombination and sensitivity to DNA damaging agents. Homologs for cohesion and condensation proteins are found in all eukaryotes which makes the study of these yeast genes relevant for understanding mitotic chromosome structure and segregation in humans. Genetic instability is a hallmark of cancer cells. Cellular defects in the DNA repair machinery and in checkpoints are known to lead to such instability and contribute to tumorigenesis. Cellular defects in the machinery that forms and modulates chromosome structure represent potentially important and uncharacterized risk factors for cancer as well as a novel targets for anti-cancer therapy.