Mechanisms of Sister Chromatid Pairing

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DESCRIPTION (provided by applicant): To produce viable progeny, cells must identify the products of chromosome replication as sister chromatids from S-phase until chromosome segregation. Sister chromatid identity is achieved by a combination of complexes: 1) cohesin tethers that maintain pairing over time, 2) deposition factors that load cohesins onto sister chromatids and 3) establishment factors that convert chromatin-associated cohesins into a paired or tethered state. All of these cohesion pathways are essential such that mutation in any one (maintenance, deposition and establishment) results in massive chromosome mis-segregation and cell death. Many of the phenotypes observed in cohesion loss mutants (aneuploidy, genome instability, defects in DNA repair, hyper- recombination and chromosomal translocations) are direct consequences of precocious sister separation and loss of a repair template - all hallmarks of cancer cells. More recent findings reveal a surprising link between cohesion defects and developmental abnormalities that include Cornelia de Lange Syndrome and Roberts Syndrome/SC Phocomelia. At the molecular level, the first establishment model posited in the literature suggested that cohesin complexes associated with each sister become tethered together through an active process that is intimately coupled to the DNA replication fork. Findings from several labs confirm the link between the establishment factor (Ctf7/Eco1) and numerous DNA replication components that include PCNA, RFC factors, and DNA helicases. Moreover, recent reports provide important clues regarding Ctf7/Eco1 acetylation-dependent conversion of cohesins to a pairing competent state and how precocious conversion (pairing) is blocked by anti-establishment factors. The Specific Aims of this R15 AREA proposal test new models of establishment by focusing on the role of both pro- and anti- establishment DNA replication factors in cohesion acetylation reactions. In addition, we test models regarding chromatin recruitment and activation of the essential establishment factor Ctf7/Eco1.) PUBLIC HEALTH RELEVANCE: Chromosomes contain the instruction manual for cells and organisms to grow and develop. For growth during embryonic development, in response to trauma or to replace cells in a harsh environment (gastro-intestinal tracts), cells must replicate their chromosomes and then divide such that each daughter cell gets an identical copy. This proposal explores new models regarding how these replicated chromosomes are properly segregated during cell division.