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    Research Grants Awarded

    Cohesion-dependent Mechanisms of Cancer Progression and Aneuploidy

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    In eukaryotes, DNA replication is separated in time from chromosome segregation, requiring that the products of chromosome replication (termed sister chromatids) produced during S-phase remain paired until mitosis. Sister chromatid pairing, or cohesion, thus ensures that the fundamental process of chromosome segregation proceeds with high fidelity. Intense research efforts have addressed the structures that hold sister chromatids together, but the mechanism by which sister chromatids first become paired together during S-phase, termed cohesion establishment, remains unknown and highly controversial. What is known is that defects in any of the factors that function in sister chromatid pairing results in massive chromosome mis-segregation, aneuploidy and cell death. In humans, it is now clear that defects in any class of cohesion factor directly result in one of many human disease states including premature aging, developmental abnormalities, mental retardation and cancer. More recently, cell phenotypes associated with mutations in BRCA1-complex components (including DNA helicase, RFCs and MRN subunits) have revealed a new role for BRCA1 in sister chromatid pairing. These cell phenotypes involve numerous chromosome aberrations that include whole chromosome duplications, translocations, inter-sister gaps and gene misregulation ? all of which are directly attributable to sister chromatid pairing defects as a causal mechanism. Analyses of an essential yeast cohesion establishment factor CTF7/ECO1 led to the discovery of novel interactions between CTF7, POL30 (PCNA) and Replication Factor C (RFC) complexes. PCNA and RFCs perform interdependent functions in DNA replication/repair and, in humans, are components of BRCA1 complexes. New evidence from model organisms that BRCA1-associated DNA helicases also bind Ctf7p and function in sister chromatid pairing provide novel evidence that cohesion-dependent chromosome aberrations directly contribute to tumorigenesis. Here, we will capitalize on successes in these fields to dissect at the molecular level how BRCA1-associated DNA replication and repair fork machineries establish cohesion between nascent sister chromatids. These studies will have a direct impact on how we view cancer progression and are likely to provide new targets to combat breast and ovarian cancers as well as a number of other cohesion-related human disease states.

    Lay Abstract:
    Cells divide to allow for embryonic growth, wound repair and to replace old or dying cells. Before a cell divides, each chromosome must be replicated to produce two sister chromatids. During chromosome replication, the resulting sister chromatids become paired together so that each can be properly segregated later during cell division. Sister chromatid pairing, or cohesion establishment, is an essential and highly regulated process that is fundamental to proper chromosome segregation and cell viability. There is now evidence that the tumor suppressor Breast Cancer Associated gene 1 (BRCA1) and BRCA1-associated factors play key roles in sister chromatid pairing mechanisms. Identification of a novel cohesion establishment pathway in both yeast and man provided new evidence that sister chromatid pairing is intimately coupled to DNA replication and repair. Findings from several labs indeed confirm that defects in pairing not only result in aneuploidy, a hallmark of cancer progression, but that loss of pairing dramatically effects DNA repair mechanisms and may generate fragile sites that promote chromosome aberrations including chromosome breakage, translocations and gene mis-expression: all of which are phenotypes of BRCA1-deficient cells. Capitalizing on current progress in the cohesion field, we are identifying the molecular machineries at the DNA replication fork and DNA repair fork required to establish sister chromatid pairing and how defects in these processes result in tumorigenesis and cancer progression.