THE TELOMERE AND TELOMERASE


THE TELOMERE AND TELOMERASE: NUCLEIC 姥ID-PROTEIN COMPLEXES ACTING IN A TELOMERE HOMEOSTASIS SYSTEM E.H. Blackburn Department of Microbiology and Immunology, and of Biochemistry and Biophysics, University of California, San Francisco, Department of Microbiology and Immunology 513 Parnassus, Room S447, Box 0414, San- Francisco, A 94143-0414; fax: (415)476-8201, E-mail: porter@itsa.ucsf.edu Submitted August 12, 1997 The tandemly repeated DNA sequence of telomeres is typically specified by the ribonucleoprotein enzyme telomerase. Telomerase copies part of its intrinsic RNA moiety to synthesize one strand of the telomeric repeat DNA. Recent work, taken together with many observations over the past years, has led to the concept of a telomere homeostasis system. We have analyzed the interplay between two key physical components of this system: structural components of the telomere itself and of telomerase. Here we review some of these recent studies. The experimental method used in common in these studies was to make mutations in the template sequence of telomerase RNA, which caused various phenotypes: First, mutating specific residues in the ciliate Tetrahymena and yeast showed that these residues are required for critical aspects of the enzymatic action of telomerase. Second, certain mutated telomeric sequences caused a strong anaphase block in Tetrahymena micronuclei. Third, specific template mutations in the telomerase RNA gene led to varying degrees of telomere elongation in Tetrahymena and the yeast K. lactis. For some of the K. lactis mutations, the loss of length unregulated elongation was directly related to loss of binding to K. lactis Rapl protein. Using K. lactis carrying alterations in the telomerase RNA template, and in the gene encoding the Raplp protein, we found that a crucial determinant of telomere length homeostasis is the nature of the duplex DNA-Raplp protein complex on the very end repeat of the telomere. We propose that this complex plays a key role in regulating access of telomerase to the telomere.

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