SISTER CHROMATID COHESION AND THE ORIGIN OF TETRAPLOIDY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Improper maintenance of ploidy (chromosome number) is a hallmark of many cancer cell types, and is thought to contribute to malignancy in cancer cell populations. In a number of tumors tetraploidy, exactly twice the normal complement of DNA, precedes a more degenerate aneusomic state in which individual chromosomes appear to be lost or gained at random. This condition is referred to as the chromosome instability, or "CIN" phenotype. Several lines of evidence strongly suggest a direct connection between defective sister chromatid cohesion (SCC) and aneuploidy in vertebrates. SCC is the process by which newly replicated chromosome copies are held together along their length until cell division. SCC is mediated by a large, multisubunit complex called cohesin. The association of this complex with chromosomes is tightly controlled by a number of regulatory proteins, DNA replication, and cell cycle progression. In order to better understand how cohesion fails, we are studying how cohesion is established and maintained in response to cell cycle progression. We are particularly interested in the mechanism of action of a protein we discovered several years ago, called sororin. Sororin is a positive regulator of SCC; RNAi-mediated depletion of sororin results in catastrophic loss of sister chromatid cohesion, and prolonged mitotic arrest due to activation of the spindle checkpoint. We are interested in how the activity of sororin is coordinated with other events that control SCC and cell division. Recent data suggest that sororin serves to maintain cohesion in G2 by recognizing and stabilizing cohesin that is in the "established" conformation. Understanding the nature of this conformation is essential to understanding how cohesion fails, leading to chromosome mis-segregation and chromosome instability.