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Interdisciplinary Biomedical Sciences Program
M.S. 2002, Mannheim University of Applied Sciences, Germany
B.M. 1999, Beijing Medical University, China
Thesis Advisor: Utz Herbig, Ph.D.
Department of Microbiology and Molecular Genetics
Thursday, March 17, 2011
Cancer Center, G Level Seminar Room, 9:30 A.M.
All human somatic cells have a limited replicative capacity in culture and will eventually undergo cellular senescence. While cellular senescence has been demonstrated to function as a potent tumor suppressing mechanism, it might also play a causative role in organismal aging. A primary reason for this terminal growth arrest is that telomeres, the physical ends of linear chromosomes, progressively shorten with every cell cycle and eventually become dysfunctional. Although the mechanisms of telomere shortening with every cell division are well understood and likely due to a combination of factors, the reasons for telomere dysfunction are not known. In this thesis we provide evidences to show that telomere dysfunction can occur in response to various stresses that do not require continuous cell proliferation.
Three different stresses including inhibition of protein synthesis, oncogenic RAS signaling and DNA replication stress were examined in human fibroblasts. It was demonstrated that telomere dysfunction indeed occurs in response to these stresses, which do not require continuous cell proliferation. Incubation of early passage human fibroblasts with protein translation inhibitors caused telomere dysfunction as early as 2 hours after drug exposure; however, hTERT-immortalized cells did not accumulate dysfunctional telomeres after treatment with protein translation inhibitors, indicating that telomerase prevents the drug-induced inactivation of protein(s) required for telomere function. Our data also demonstrate that oncogenic H-RAS V12 causes telomere dysfunction and fragile telomeres in normal human fibroblasts. DNA replication stress induced by HU treatment was shown to cause telomere dysfunction in normal human fibroblasts, which suggests that H-RAS induced cellular senescence probably by promoting DNA replication stress induced telomere dysfunction. Taken together, our data indicate that telomeres are highly sensitive structures that rapidly become dysfunctional in response to a variety of stresses which likely do not significantly alter telomere length. The study of this thesis will reveal some novel mechanisms that rapidly induce dysfunctional telomeres upon encountering stresses without the requirement of telomere shortening.