The goal of this research proposal is to elucidate the mechanisms that regulate sister telomere cohesion in human cells. Telomeres are unique heterochromatic structures that require specialized mechanisms for their replication, protection, and cohesion. Establishment of cohesion between sister telomeres in S phase is essential for homologous recombination and DNA repair in G2 phase of the cell cycle and timely resolution of cohesion between sister telomeres at mitosis is critical for genome integrity. Our studies in human cells have shown that sister telomeres require distinct mechanisms (compared to sister arms and centromeres) for cohesion establishment in S phase and resolution in mitosis. Here we seek to elucidate the underlying mechanisms.
In Aim 1 we will determine how cohesion is established at telomeres and why it is important.
In Aim 2 we will determine how cohesion is removed from telomeres at mitosis and what happens if it is not. And in Aim 3 we will explore a novel hypothesis (based upon our new preliminary data) that persistent cohesion at mitosis is a general cellular mechanism for dealing with telomere dysfunction. !

Public Health Relevance

Project Narrative Telomeres, the ends of chromosomes, play a crucial role in chromosome stability and genome integrity. Telomere dysfunction contributes to aging, cancer, and other human diseases, including dyskeratosis congenital an inherited bone marrow failure disease. The results from this project will reveal how telomere function is maintained in human cells and will thus impact our understanding of human disease and contribute to therapeutics in cancer and aging.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA116352-06
Application #
8302711
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Pelroy, Richard
Project Start
2005-07-01
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$312,389
Indirect Cost
$128,089
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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
Canudas, Silvia; Houghtaling, Benjamin R; Bhanot, Monica et al. (2011) A role for heterochromatin protein 1? at human telomeres. Genes Dev 25:1807-19
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
Hsiao, Susan J; Smith, Susan (2009) Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ. J Cell Biol 184:515-26
Hsiao, Susan J; Smith, Susan (2008) Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 90:83-92
Canudas, Silvia; Houghtaling, Benjamin R; Kim, Ju Youn et al. (2007) Protein requirements for sister telomere association in human cells. EMBO J 26:4867-78