National Academy of Sciences
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Election Year: 1993
Primary Section: 21, Biochemistry
Membership Type: Foreign Associate
My research program focuses on the structure, function, and synthesis of telomeres. These are the natural ends of linear chromosomes in eukaryotes and consist of DNA-plus-protein structures that protect the ends of chromosomes from damage and DNA loss. We showed that the DNA sequences of telomeres are synthesized by a widely conserved, novel, ribonucleoprotein enzyme called telomerase. The RNA part of telomerase contains a short-template sequence that is copied over and over again into repeated telomeric DNA. This was confirmed by studies in the test tube and in living cells. This work established that telomerase is a specialized reverse transcriptase of normal cells. Unlike reverse transcriptases of viruses, the integral RNA of telomerase plays key roles in enzyme action. We are studying how telomerase activity is built up from this novel collaboration between telomerase protein and RNA. In genetic experiments we showed that certain telomerase RNA mutants cause telomere shortening and senescence in Tetrahymena and a yeast, the first demonstration that impairing telomerase can lead to cellular senescence. In human cancer cells grown in the laboratory, we showed that chemical inhibitors of telomerase caused telomeres to shorten. Other mutations of telomeres cause telomeres to get too long or cause cells to stop dividing in anaphase in the cell cycle; we are analyzing the mechanism for these.