Telomere recombination and regulation
Date
2012
Authors
Eadaim, Abdunaser Omar, author
Bailey, Susan M., advisor
Laybourn, Paul, committee member
Paule, Marvin R., committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Telomeres, tandem arrays of repetitive G-rich sequence at the physical ends of linear chromosomes, serve to protect chromosomal termini from enzymatic activity and prevent recognition of natural DNA ends as double strand breaks (DSBs). The telomeric Shelterin complex and other associated proteins play critical roles in maintaining stability of the telomere. Telomere length can be maintained by telomerase enzymatic activity or by an alternative lengthening of telomere (ALT) recombination based mechanism, which has been characterized by increased frequencies of telomere sister chromatid exchange (T-SCE). Telomeres have been shown to be especially sensitive to oxidative stress and ultraviolet (UV)-induced DNA damage, for example cyclobutane pyrimidine dimers (CPDs) between two adjacent pyrimidines. In this project, exposure to ultraviolet C (UVC) was evaluated for its ability to induce sister chromatid exchange (SCE) in cell lines with different telomerase status. Our results showed that sister chromatid exchanges, both genome-wide (G-SCE) and within telomeres (T-SCE), were increased in a dose-dependent manner following UVC exposure in telomerase negative normal human fibroblast (BJ1) and ALT human dermal fibroblasts. However, in telomerase positive human fibroblasts, while G-SCE frequencies increased in response to UVC, T-SCE frequencies did not. These results have important implications not only for aging, but for carcinogenesis as well, since UV exposure from the sun (and tanning beds) is linked to increased risk of both aging of the skin and skin cancer. The susceptibility of telomeric DNA to oxidative stress and the dampened DNA damage response in this region provide likely explanations for the increased frequencies of T-SCE observed following UV exposure. Although certainly not the only contributor, T-SCE themselves provide intriguing insight into possible mechanisms of increased telomere shortening, senescence, and carcinogenesis, and may therefore represent informative biomarkers of aging and cancer.