Professor, Skirball Institute of Biomolecular Medicine, Molecular Pathogenesis. Department of Pathology. Coord Molecular Pathogenesis Program
Ph.D., 1990 SUNY Stony Brook
Cancer, Genome Integrity, Telomeres, Sister Chromatid Cohesion
Skirball Institute of Biomolecular Medicine
540 First Avenue 2nd floor, Lab 9
New York, N.Y. 10016
Office Tel: (212) 263-2540
Lab Tel: (212) 263-2541
Fax: (212) 263-5711
Tel: (212) 263-6281
Telomere Function in Aging, Stem Cells, and Cancer
Faithful duplication and segregation of DNA are essential for the continuity of life. Errors in chromosome replication and segregation can lead to aneuploidy, which can have serious consequences for human growth and development, and drive cancer in somatic cells. Telomeres, the ends of eukaryotic chromosomes, require special mechanisms for their protection, replication, and cohesion. We study human telomeres and the mechanisms that control their function in normal cells, stem cells, and in cancer. Human telomere function is regulated by the dedicated six-subunit telomere-binding complex shelterin and by a number of other shelterin-binding factors, such as the poly(ADP-ribose) polymerase tankyrase 1, that associate transiently with telomeres. The goal of our research is to understand how shelterin and its accessory factors regulate telomere structure and function, and control access to telomerase, the reverse transcriptase that adds telomere repeats to chromosome ends. We have several areas of focus in the lab: 1) the regulation of shelterin stability and function by post-translational modification, including poly(ADP-ribosyl)ation, and ubiquitylation and proteasomal degradation; 2) the mechanisms that control the establishment of sister chromatid cohesion at telomeres during DNA replication and the resolution of sister chromatid cohesion at telomeres in mitosis; 3) the role of defective telomere cohesion in the human stem cell disease dyskeratosis congenita; and 4) the cell cycle regulation and non-telomeric functions of tankyrase 1, including its role at spindle poles and centrosomes. Our long-term goal is to understand the mechanisms that ensure genome integrity and cell survival.
Ramamoorthy M, Smith S. (2015) Loss of ATRX Suppresses Resolution of Telomere Cohesion to Control Recombination in ALT Cancer Cells. Cancer Cell,14;28(3):357-69. PubMed PMID: 26373281.
- Smith S. (2015) PARP Inhibitors for Cancer Therapy. Curtin N, Sharma R, editors. New York: Springer. TIPs: Tankyrase Interacting Proteins; p.79-98.
- Kim, M.K. and Smith, S. (2014) Persistent telomere cohesion triggers a prolonged anaphase. Molecular Biology of the Cell, 25(1):30-40. PMID: 24173716
Bisht KK, Daniloski Z, Smith S. (2013) SA1 binds directly to DNA through its unique AT-hook to promote sister chromatid cohesion at telomeres. J Cell Sci. 2013 Aug 1;126(Pt 15):3493-503. PMID: 23729739
- Kim, M.K., Dudognon, C., and Smith, S. (2012) Tankyrase 1 regulates centrosome function by controlling CPAP stability. EMBO Reports, 13(8):724-732. PMID: 22699936