Smith Lab

Research Summary:  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, aged cells, and 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. We have several areas of focus in the lab: 1) the regulation of tankyrase and shelterin stability and function by post-translational modification, including poly(ADP-ribosyl)ation, ubiquitylation, and proteasomal degradation; 2) the mechanisms that control the establishment and resolution of sister chromatid cohesion at telomeres and ribosomal DNA repeats; 3) the role of telomere cohesion in senescence in human aged cells and in telomere maintenance in ALT (Alternative Lengthening of Telomeres) cancer cells. Our long-term goal is to understand the mechanisms that ensure genome integrity and cell survival.