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Telomeres are located at the ends of eukaryotic linear chromosomes and are composed of repeated nucleotide sequences. The main function of telomeres is to protect chromosomal ends. However, telomeres cannot be copied entirely during DNA replication leading to a gradual shortening known as the “end-replication problem”. To counteract this problem, the RNA-dependent enzyme complex telomerase works to extend telomeres and maintain the chromosomal ends which helps to prevent senescence. Understanding the structure and function of telomerase could have important implications for the development of anti-cancer therapeutics, since telomerase is over-active in >85% of all human cancers. While the general role of the telomerase enzyme is known, much about the roles of individual factors remains elusive. We are interested in better understanding the function of rapidly-evolving telomerase RNA. Most past research ascribed telomerase RNA function through identifying loss-offunction mutations that abolish enzyme function. In contrast, we set out to identify novel gain-of-function mutations that increase enzyme activity. To this end, we designed an elegant genetic screen in the model organism Saccharomyces cerevisiae that allows us to select more active versions of telomerase RNA from a pool of 5,000 random mutations.

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Enhancing telomerase activity in Saccharomyces cerevisiae through a genetic screen for gain-of-function mutations



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