Journal
FEBS JOURNAL
Volume 280, Issue 14, Pages 3194-3204Publisher
WILEY
DOI: 10.1111/febs.12272
Keywords
biogenesis regulation; enzyme assembly; intracellular trafficking; nucleotide addition processivity; structure-activity relationship; subcellular localization; telomere catalysis; telomerase reverse transcriptase; telomerase RNA; repeat addition processivity
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Funding
- Canadian Cancer Society Research Institute [019250]
- Michael Smith Foundation for Health Research [CI-SCH-00102]
- Canadian Institutes of Health Research [FRN85515]
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Telomeres are nucleoprotein structures found at the ends of linear chromosomes. Telomeric DNA shortens with each cell division, effectively restricting the proliferative capacity of human cells. Telomerase, a specialized reverse transcriptase, is responsible for denovo synthesis of telomeric DNA, and is the major physiological means by which mammalian cells extend telomere length. Telomerase activity in human soma is developmentally regulated according to cell type. Failure to tightly regulate telomerase has dire consequences: dysregulated telomerase activity is observed in more than 90% of human cancers, while haplo-insufficient expression of telomerase components underlies several inherited premature aging syndromes. Over the past decade, we have significantly improved our understanding of the structure-activity relationships between the two core telomerase components: telomerase reverse transcriptase and telomerase RNA. Genetic screening for telomerase deficiency syndromes has identified new partners in the biogenesis of telomerase and its catalytic functions. These data revealed a level of regulation complexity that is unexpected when compared with the other cellular polymerases. In this review, we summarize current knowledge on the structure-activity relationships of telomerase reverse transcriptase and telomerase RNA, and discuss how the biogenesis of telomerase provides additional regulation of its actions.
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