Cells must identify the products of chromosome replication, termed sister chromatids, from S-phase until anaphase onset. However, the mechanism that first pairs sister chromatids together remains unknown. CTF7/ECO1 is the founding member of a cohesion establishment pathway and appears to couple sister chromatid pairing reactions to DNA replication. Sister pairing can also be induced outside of S-phase, suggesting that Ctf7p establishment activity is tightly regulated. Currently, Ctf7p remains the only essential establishment factor known. Recent findings confirm that Ctf7p functions during S-phase, is recruited to chromatin during S-phase and binds to numerous chromatin-associated replication factors. In Phase 1, we will use site-directed mutational analyses coupled to biochemical methodologies to identify which protein interactions are required for Ctf7p chromatin recruitment and how Ctf7p recruitment/activation is regulated. Genetic and molecular analyses will then be paired to high-resolution microscopy cohesion assays to test for the role of novel alleles in cell viability and in sister pairing reactions. In Phase 2, we will identify how Ctf7p pairs sister chromatids once recruited to chromatin. We will pursue results from our lab that Ctf7p associates with Pds5p, a cohesin regulator that is required to maintain sister pairing. Ctf7p-Pds5p binding is the only known link between the processes that establish and maintain cohesion. To address these issues, we will use biochemical and cell-cycle mapping strategies to test if Ctf7p-Pds5p binding is cell cycle specific, direct and essential. Both Ctf7p and Pds5p are post-translationally modified. Molecular and biochemical methodologies will be used to determine how Ctf7p-Pds5p establishment activity is regulated over the cell cycle, regulate binding and ultimately how Ctf7p- Pds5p affect cohesin dynamics on chromatin. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Nuclear Dynamics and Transport (NDT)
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Carter, Anthony D
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Lehigh University
Schools of Arts and Sciences
United States
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Tong, Kevin; Skibbens, Robert V (2015) Pds5 regulators segregate cohesion and condensation pathways in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 112:7021-6
Tong, Kevin; Skibbens, Robert V (2014) Cohesin without cohesion: a novel role for Pds5 in Saccharomyces cerevisiae. PLoS One 9:e100470
Rudra, Soumya; Skibbens, Robert V (2013) Cohesin codes - interpreting chromatin architecture and the many facets of cohesin function. J Cell Sci 126:31-41
Skibbens, Robert V; Colquhoun, Jennifer M; Green, Megan J et al. (2013) Cohesinopathies of a feather flock together. PLoS Genet 9:e1004036
Rudra, Soumya; Skibbens, Robert V (2013) Chl1 DNA helicase regulates Scc2 deposition specifically during DNA-replication in Saccharomyces cerevisiae. PLoS One 8:e75435
Rudra, Soumya; Skibbens, Robert V (2012) Sister chromatid cohesion establishment occurs in concert with lagging strand synthesis. Cell Cycle 11:2114-21
Skibbens, Robert V; Marzillier, Jutta; Eastman, Laura (2010) Cohesins coordinate gene transcriptions of related function within Saccharomyces cerevisiae. Cell Cycle 9:1601-6
Skibbens, Robert V (2010) A sliding scale: the many faces of Ctf7/Eco1 cohesion establishment factor in DNA repair. Cell Cycle 9:3642-3
Maradeo, Marie E; Garg, Anisha; Skibbens, Robert V (2010) Rfc5p regulates alternate RFC complex functions in sister chromatid pairing reactions in budding yeast. Cell Cycle 9:4370-8
Maradeo, Marie E; Skibbens, Robert V (2010) Replication factor C complexes play unique pro- and anti-establishment roles in sister chromatid cohesion. PLoS One 5:e15381

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