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Senior Scholar Award in Aging
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Carol W.
Greider,
Ph.D.
Johns Hopkins University School of Medicine
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The Roles of Recombination and Telomerase in Telomere Maintenance.
Telomerase is the predominant mechanism that allows telomere length
maintenance in eukaryotic cells. Telomerase activity is up-regulated in over 90%
of human tumors suggesting that this enzyme is necessary for tumor cell growth.
Evidence from human and mouse cells suggests that telomerase inhibition will lead
to cell death and may be a useful approach to cancer chemotherapy. However,
work in yeast has shown that when telomerase activity is eliminated,
recombination mediated pathways for telomere maintenance can still allow cell
survival. Over the past five years evidence has accumulated that such
recombination-based pathways also may function in human and mouse cells
where telomerase is absent. Thus, if telomerase inhibition is to be seriously
considered as a therapeutic approach to cancer treatment, it is essential to
determine whether these bypass mechanisms will allow the continued growth of
tumors and selection for telomerase inhibitor resistant cells in vivo. To test
whether recombination will play a role in the growth of tumor cells in the absence
of telomerase, we are crossing the telomerase null mouse to several
recombination deficient animals. mTR-/- mice, that lack the RNA component of
telomerase, are viable for 6 generations, and show progressive telomere
shortening. After five to six generations, telomere shortening severely
compromises the ability of many cell types to survive. However, once
transformed, these telomerase null cells can still form tumors in vivo. We will
determine whether a deficiency in recombination will reduce the ability of these
cells to form tumors in the absence of telomerase. These studies will allow a more
complete understanding of the role of both recombination and telomerase in
telomere maintenance and may lead to more sophisticated approaches to
telomerase inhibition therapies.
Contact
Dr. Greider.
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