The roles of recombination and telomerase in telomere maintenance
1998 Senior Scholar in Aging Award

We are interested in understanding how cells maintain their chromosomes, the structures that transmit genetic information. Specifically, we are interested in the ends of chromosomes, known as telomeres. Telomeres are specialized structures that are essential for the chromosomes maintenance. When chromosomes are not properly maintained, diseases such as cancer can result. Telomeres are synthesized by the enzyme telomerase. Telomerase is present in the developing organism but is turned off in most adult cells. In the absence of telomerase, telomeres shorten every time a cell divides. Therefore, chromosomes from younger individuals are generally longer than those from older individuals. Unlike most normal adult tissues, most human tumors have detectable telomerase activity. The presence of telomerase in cancer cells and its absence in most normal cells has made telomerase an attractive target for cancer therapy. There are tumor cells however, that maintain chromosomes in the absence of telomerase. We are testing mouse models to understand how telomerase-independent telomere maintenance works and whether it will have an impact in cancer.

Researchers
Carol W. Greider Ph.D.
Johns Hopkins University

In this project, Dr. Greider pursued the mechanisms by which telomere length and integrity are maintained in the living cell. In cancer, most human tumors exhibit evidence of telomerase enzyme activity. But in rare instances, as in tissue culture, when telomerase is not present, other mechanisms arise to allow unlimited cell division, conferring the "immortality" that is characteristic of tumor cells. This phenomenon is called ALT (for alternative telomere maintenance). In yeast, recombination has been shown to serve as a "bypass" mechanism for maintaining telomeres in the absence of telomerase. In certain human cell lines in which telomeres are maintained without apparent telomerase activity, recombination has been thought to be involved, but proof was lacking. Dr. Greider and her team worked with mice that lacked the ability to produce telomerase, and created mice that lacked both telomerase and a gene involved in recombination. In preliminary experiments, lack of these two telomere maintenance pathways did not explicitly prevent tumor formation. The team also found by using metaphase spreads that ultra-short telomeres are associated with abnormal chromosome fusions, translocations and fragmentation, going beyond "average" telomere shortening.