Robert A. Marciniak, M.D., Ph.D.Associate Professor
Our research centers on the basic biology of aging and cancer, emphasizing the interrelationship between the two. Initially we have taken a genetic approach, and have focused on the analysis of a progeriod disorder, Werner syndrome. Werner syndrome is a human autosomal recessive disorder characterized by symptoms suggestive of premature aging and a predisposition to cancer. Our analysis of the molecular defect that causes Werner syndrome has led to the study of its involvement in telomere processing. We are currently investigating the role that the Werner syndrome helicase (WRN) may play in telomere maintenance and how the loss of the function of this protein and dysfunctional telomere processing - can lead to both symptoms of premature aging and increased cancer incidence.
We are currently utilizing a variety of approaches to probe the function of Werner protein at telomeres in primary and immortalized cells. Projects currently underway include: (1) The analysis of the interaction of WRN with telomere repeat binding factor 2 (TRF2) and the Fanconi anemia subgroup G protein. These proteins were identified as potential WRN interacting proteins utilizing a yeast two-hybrid screen. (2) The requirement for the function of the Werner protein for telomere maintenance is being tested through the construction of cell lines that contain an inducible, dominant-negative form of the protein. (3) The involvement of the Werner protein in DNA repair pathways is being studied using fluorescent protein reporter constructs.
Marciniak, R.A. (2001) Genomic instability and yeast aging. In Chromosomal Instability and Aging: Basic Science and Clinical Implication, G. Martin, S. Weissman, and F. Hisami, eds. (New York, Marcel Dekker, Inc), In Press.
Johnson F.B., Marciniak R.A., McVey M., Stewart S.A., Hahn W.C., and Guarente L. (2001) The S. cerevisiae WRN homologue Sgs1p participates in telomere maintenance in cells lacking telomerase. EMBO J 20:905-913.
Marciniak R.A., Lombard D.B., Johnson F.B. and Guarente L. (1998) Nucleolar localization of the Werner syndrome protein in human cells. Proc Natl Acad Sci USA 95:6887-6892.