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Phenotypes Occuring in Saccharomyces cerevisiae Early after Telomerase Inactivation

  • Author(s): Jay, Kyle Aaron
  • Advisor(s): Blackburn, Elizabeth H
  • et al.
Abstract

Telomeres are DNA and protein complexes that cap the ends of linear chromosomes. These caps serve two primary functions: to buffer against the loss of terminal DNA sequences resulting from the end replication problem and to conceal chromosome ends from the cellular DNA damage response (DDR) and inappropriate repair events. Telomeres are maintained by telomerase, a multi-component ribonucleoprotein complex with reverse transcriptase activity. Saccharyomyces cerevisiae cells constitutively express telomerase, allowing nearly unlimited growth of the bulk population. However, when telomerase activity is removed from Saccharyomyces cerevisiae cells, telomeres shorten over time and cells can continue to divide for approximately 60-80 cell divisions before chromosome ends lose their protective cap and initiate a permanent cell cycle arrest known as senescence. It had previously been believed that these cells lacking telomerase activity grow indistinguishably from wild-type cells until telomeres begin to reach a critically short length. However, I will show that even Early after Telomerase Inactivation (ETI), cells lacking telomerase activity display numerous detrimental phenotypes. ETI cells displayed altered cell cycle kinetics and a dependence on certain DDR components for full viability. ETI cells also displayed an acceleration of mother cell aging, a process by which yeast mother cells cease to produce daughters after a certain number of divisions and which has not previously been shown to interact with telomere maintenance pathways. These phenotypes occurred independently of telomere length and were rescued by elevated nucleotide pools resulting from deletion of Sml1, an inhibitor of ribonucleotide reductase. This suggests that ETI cells struggle to resolve telomeric DNA replication stress. ETI cells were also sensitive to downregulation of TOR kinases, which have diverse roles in metabolic and structural regulation of the cell. These findings suggest that telomerase is required for more than the counteraction of the slow erosion of telomere ends. Telomerase functions extend to the relief of telomeric DNA replication stress, maintenance of normal healthy lifespan, and interactions with other diverse cellular pathways.

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