Identifying the Molecular Determinants of Chromosome Stability in Humans.

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Understanding the molecular bases and processes that impact chromosome stability is of critical importance to all living organisms. Many of the biological processes that impact chromosome stability are inherently conserved throughout evolution, and include DNA replication, repair and chromosome segregation during cellular division. Consequently, information gleaned in model organisms such as yeast, flies and worms can be used to identify candidates to evaluate in a human context. Unbiased and genome-wide approaches have in the past been limited to genetically tractable models such as yeast and have generated lists of chromosome stability genes - many of which remain to be fully characterized. What's more, even less is known about the corresponding human counterparts particularly with respect to their roles in chromosome stability or the underlying mechanism. Recent advancements in genetic approaches, reagents and equipment have now made it possible to perform large-scale analyses in human cell lines. We recently employed a focused cross-species approach and identified new human chromosome stability genes. We subsequently demonstrated that a subset of these genes products are required for sister chromatid cohesion, an essential biological process in which newly replicated chromosomes are held in close together prior to cellular division. Defective sister chromatid cohesion adversely affects chromosome stability by allowing for the inaccurate segregation of genetic material into each daughter cell. We now seek to greatly expand these initial studies by developing an innovative and high-throughput approach in which we will evaluate chromosome stability for candidate human genes identified in cross-species approaches. By coupling state-of-the-art molecular imaging with cutting-edge genetic and biochemical techniques we will rapidly interrogate candidates and produce a refined list of human chromosome stability genes. In turn, these genes will become the subjects of subsequent studies designed to further characterize their specific functional roles in maintaining chromosome stability and will vastly expand current knowledge pertaining to a pivotal biological process that is essential in all living organisms.