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Paula Green
Pharmacology & Physiology Program
B.S 2001, Haverford College

Thesis Advisor: Janine Santos, Ph.D.
Assistant Professor
Department of Pharmacology & Physiology

Friday, June 13, 2014
12:00 P.M. , MSB Room H-609b


Telomerase is a ribonucleoprotein fundamentally responsible for telomere maintenance that is a frequent target in cancer research. It has been established that the catalytic component of telomerase (hTERT) is also mitochondrial. It can be postulated that telomerase inhibition not only can affect telomere biology, but can likewise interfere with proper mitochondrial function. The function of hTERT in mitochondria is still unknown but it is evident through our study that it plays a role in the response of cells to oxidative stress. Work done by our group has shown that cells carrying wild type (WT) hTERT have increased mtDNA damage and undergo more cell death upon exposure to hydrogen peroxide (H2O2). These effects depend on the mitochondrial localization of the protein since reduction in mtDNA damage and apoptosis were observed in cells carrying a non-mitochondrial hTERT mutant under same treatment conditions. However, the mechanism through which mitochondrial hTERT can influence the cellular response to oxidative stress remains unclear. Autophagy has become increasingly accepted as an additional means to maintain proper mitochondrial function, relying on the clearance of damaged organelles. When monitoring this process, we found that markers of autophagy are not activated in cells expressing WT hTERT, while significantly increased in cells carrying the non-mitochondrial mutant. Reintroduction of the mitochondrial pool of hTERT in mutant cells reversed the autophagic response under oxidative stress. Furthermore, we also found that the activation of autophagy in mutant-expressing cells was mitochondrially-ROS dependent. Taken together, our results indicate that the loss of hTERT in mitochondria sets in motion a signaling cascade that allows cells to adapt to and cope with the lack of mitochondrial telomerase. Our results unveil new details about the role of telomerase in cells and the potential impact of its overall inhibition in cancer.

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