Susan Smith, PhD

Susan SmithProfessor of Pathology
PhD 1990 SUNY Stony Brook

Skirball Institute of Biomolecular Medicine
New York University School of Medicine
540 First Avenue 2nd floor
New York, New York  10016
Tel: (212) 263-2540
E-mail: susan.smith@med.nyu.edu

Lab website: http://saturn.med.nyu.edu/research/mp/smithlab/
Research Theme(s): Human Telomere Biology, Telomere Function in Stem Cells and Disease, Telomere Function in Aging and Cancer
Keywords: Telomeres, Shelterin, Dyskeratosis Congenita, Sister Telomere Cohesion

Research Summary:

Telomere integrity is essential for chromosome stability and cell proliferation. Telomeric sequences are lost with each round of DNA replication, but this loss can be counteracted by the enzyme telomerase. In humans telomerase is expressed in the germ line and the embryo, but is repressed in the soma and as a result telomeres shorten. This shortening leads to a DNA damage signal at telomeres and results in cellular senescence. In contrast to somatic tissues, most adult human stem cells display low levels of telomerase activity. Yet despite these levels of telomerase, adult stem cells exhibit telomere shortening, indicating that low levels are not sufficient to maintain telomere length. Thus, the proliferative capacity of stem cells is limited by telomere shortening. This is well illustrated by the human stem cell disease dyskeratosis congenita (DC), where mutations in telomerase subunits result in accelerated telomere shortening, stem cell depletion, bone marrow failure, and premature death.

In addition to telomerase, shelterin, a six-subunit complex that localizes to human telomeres, is required for telomere length maintenance and chromosome end protection. A focus of my lab has been to dissect the functional contribution of the individual shelterin subunits to telomere function. The shelterin subunit TIN2 is at the heart of the shelterin complex with binding sites to the three of the other subunits. TIN2 regulates telomere elongation by telomerase. Over the last few years my lab has uncovered a novel function for TIN2: it is required to keep sister chromatids cohered following DNA replication. We showed that cells depleted of TIN2 were unable to repair DNA breaks in G2 and suffered sister telomere loss. These results turn out to have significant impact on our understanding of DC. Recent studies have shown that in addition to telomerase, TIN2 is mutated in a subset of cases of DC, but the mutations fall outside TIN2’s shelterin subunit binding sites. Patients harboring TIN2 mutations have extremely short telomeres (shorter than telomerase mutations), correlating with early age of presentation and severe clinical presentation, but the reason for the severity was not known.

We have found that the DC mutation cluster in TIN2 harbors a binding site for the heterochromatin protein HP1. We showed that all the TIN2 DC mutations abrogate binding to HP1 and that HP1 (like TIN2) is required for telomere cohesion. Furthermore, we found that skin fibroblasts from TIN2 DC patients displayed defects in telomere cohesion. We suspect that these defects contribute to the severe phenotype of these patients. In our future studies we will continue to investigate the molecular mechanisms and the consequences of defective telomere cohesion. In addition, we will determine if we can rescue the slow growth and senescence observed in TIN2 DC patient cells by expressing wild type TIN2 and by using induced pluripotent stem (iPS) cell approaches. Our experiments will shed light on telomere function in human stem cells and disease.

Selected publications (2006-2011):