MECHANISMS OF SISTER TELOMERE COHESION AND RESOLUTION Faithful duplication and segregation of DNA are essential for the continuity of life. Errors in chromosome segregation can lead to aneuploidy and drive cancer in somatic cells. To ensure accurate distribution of chromosomes to daughter cells, sister chromatids are held together from the time of their replication in S phase until their separation in mitosis by proteinaceous bridges called cohesins. Dissociation of cohesins is regulated by two distinct pathways, one acting on chromosome arms and the other on centromeres. We have recently discovered a third pathway, which acts on telomeres. In tankyrase 1 deficient cells arms and centromeres separate normally, but telomeres remain associated, resulting in an early anaphase arrest. Our studies suggest that replicated, cohered telomeres uniquely require tankyrase 1 and its catalytic PARP [poly (ADP-ribose) polymerase] activity for their resolution. The goal of this research proposal is to identify the molecular components that hold sister telomeres together and to elucidate the mechanisms that resolve this association. To achieve these goals we will (1) characterize the association of cohesins with telomeres, focusing on our newly identified interaction between the cohesin subunit SA1 and the telomeric subunit TRF1, (2) determine the role of condensins in resolving sister telomere cohesion, focusing on our newly identified interaction between condensin I and the telomeric complex containing TRF1, and (3) determine the precise timing and control of sister telomere resolution. Additionally, in all three aims we will investigate the role of tankyrase 1 in resolution of sister telomeres. Relevance: To ensure accurate transmission of genetic material to daughter cells, replicated sister chromatids are held together by protein complexes called cohesins. Mistakes in sister chromatid cohesion are a major driving force in human cancers. Thus, understanding the mechanisms that govern cohesion will be highly relevant to human disease. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Genetics C Study Section (MGC)
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Okano, Paul
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New York University
Schools of Medicine
New York
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Smith, Susan (2018) Telomerase can't handle the stress. Genes Dev 32:597-599
Tripathi, Ekta; Smith, Susan (2017) Cell cycle-regulated ubiquitination of tankyrase 1 by RNF8 and ABRO1/BRCC36 controls the timing of sister telomere resolution. EMBO J 36:503-519
Lin, Jiangguo; Countryman, Preston; Chen, Haijiang et al. (2016) Functional interplay between SA1 and TRF1 in telomeric DNA binding and DNA-DNA pairing. Nucleic Acids Res 44:6363-76
Ramamoorthy, Mahesh; Smith, Susan (2015) Loss of ATRX Suppresses Resolution of Telomere Cohesion to Control Recombination in ALT Cancer Cells. Cancer Cell 28:357-69
Kim, Mi Kyung; Smith, Susan (2014) Persistent telomere cohesion triggers a prolonged anaphase. Mol Biol Cell 25:30-40
Bisht, Kamlesh K; Daniloski, Zharko; Smith, Susan (2013) SA1 binds directly to DNA through its unique AT-hook to promote sister chromatid cohesion at telomeres. J Cell Sci 126:3493-503
Bhanot, Monica; Smith, Susan (2012) TIN2 stability is regulated by the E3 ligase Siah2. Mol Cell Biol 32:376-84
Houghtaling, Benjamin R; Canudas, Silvia; Smith, Susan (2012) A role for sister telomere cohesion in telomere elongation by telomerase. Cell Cycle 11:19-25
Boehler, Christian; Gauthier, Laurent R; Mortusewicz, Oliver et al. (2011) Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. Proc Natl Acad Sci U S A 108:2783-8
Canudas, Silvia; Smith, Susan (2009) Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells. J Cell Biol 187:165-73

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