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Dimerization of Telomerase RNA During Telomerase Biogenesis Regulates Telomerase Activity

  • Author(s): Matsuguchi, Tetsuya
  • Advisor(s): Blackburn, Elizabeth H
  • et al.
Abstract

Telomerase is a ribonucleoprotein complex minimally composed of telomerase reverse transcriptase and telomerase RNA, which contains the template region encoding the telomeric repeat sequence. This minimal, monomeric complex is active for extending telomeric substrates in vitro, but several studies have indicated that telomerase reverse transcriptase as well as telomerase RNA can physically and functionally oligomerize or dimerize; however, the functional significance of dimerization is not known. Here we show that physical interaction between two (or more) molecules of the yeast telomerase RNA, TLC1, occurs in vivo by two independent modes: one involving the 3' region of TLC1 and the other by a Ku- and Sir4-mediated interaction. This telomerase RNA dimerization seems to be at least partially independent of the formation of the telomerase complex; in fact, no direct evidence for telomerase reverse transcriptase dimerization was found in our attempts. I propose a model in which TLC1 dimerization is an intermediate step during its biogenesis, and that the active telomerase complex either only has one catalytic site or that forms a dimer only transiently. Previous studies have shown that the template regions of two telomerase RNAs functionally interact, in yeast as well as in human. I have shown that Est1 and Est3, essential factors for in vivo telomerase activity, are required for this functional interaction of the telomerase RNA templates in telomeric DNA synthesis. By integrating these results, I propose a model in which TLC1 physical dimerization can obscure the template region, and the activation of telomerase activity requires uncovering of this region. I suggest that Est1 and Est3 play a role in this step. Taken together, this provides a model in which yeast telomerase dimerization during its biogenesis requires subsequent reorganization and can act as a regulatory step in telomerase activity activation.

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