Human telomeres are comprised of TTAGGG repeats and a multisubunit protein complex termed shelterin that is required for the replication and protection of chromosome ends. Tankyrase 1 is a poly(ADP-ribose) polymerase (PARP) that regulates shelterin structure and function at telomeres. Tankyrase 1 poly(ADP- ribosyl)ates (PARsylates) the shelterin DNA-binding subunit TRF1, which leads to TRF1 ubiquitination and degradation, and to telomere elongation by telomerase. In addition to its role in telomere length regulation, tankyrase 1 is required after DNA replication in the G2 phase of the cell cycle to resolve cohesion between sister telomeres. Moreover, tankyrase 1 depletion leads to cell cycle arrest (in mitosis or in G1) dependent on the cell type. Thus, tankyrase 1 plays a key role in the replication of telomeres, the processing of replicated sister telomeres and cell cycle progression. Tankyrase 1 has the added complexity that it has a closely related homolog, tankyrase 2 (with which it may be redundant), as well as multiple binding partners and subcellular localizations that vary with the cell cycle. In this proposal we will first, elucidate the function of tankyrase 1 at telomeres and in cell cycle progression in normal human cells and tumor cells. Second, we will elucidate the function of tankyrase 2, including redundancy with tankyrase 1 and non telomere functions of tankyrases in human and mouse cells. And third, we will elucidate the regulation and function of tankyrase 1 by characterizing its binding partners and phosphorylation across the cell cycle. Understanding tankyrase 1 (and 2) function will provide insights into the molecular basis of telomere function and in addition may also reveal underlying connections that coordinate telomere function and cell cycle progression. Since telomere integrity plays a key role in aging and cancer, insights gained from this work will be relevant to clinical strategies in aging and cancer.

Public Health Relevance

Telomeres (the ends of chromosomes) play a central role in aging and cancer. Understanding the proteins (such as tankyrase 1 and 2) that regulate telomere function in normal human cells and cancer cells will provide a framework for clinical strategies. Tankyrases can be inhibited by small molecule inhibitors and will thus be useful targets for clinical therapies in aging and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095099-10
Application #
8433264
Study Section
Special Emphasis Panel (ZRG1-BDA-A (02))
Program Officer
Pelroy, Richard
Project Start
2002-04-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$264,922
Indirect Cost
$108,626
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Hsiao, Susan J; Smith, Susan (2009) Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ. J Cell Biol 184:515-26
Chiang, Y Jeffrey; Hsiao, Susan J; Yver, Dena et al. (2008) Tankyrase 1 and tankyrase 2 are essential but redundant for mouse embryonic development. PLoS One 3:e2639
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
Hsiao, Susan J; Poitras, Marc F; Cook, Brandoch D et al. (2006) Tankyrase 2 poly(ADP-ribose) polymerase domain-deleted mice exhibit growth defects but have normal telomere length and capping. Mol Cell Biol 26:2044-54
Chang, William; Dynek, Jasmin N; Smith, Susan (2005) NuMA is a major acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in mitosis. Biochem J 391:177-84
Dynek, Jasmin N; Smith, Susan (2004) Resolution of sister telomere association is required for progression through mitosis. Science 304:97-100
Houghtaling, Benjamin R; Cuttonaro, Leanora; Chang, William et al. (2004) A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol 14:1621-31
Chang, William; Dynek, Jasmin N; Smith, Susan (2003) TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev 17:1328-33