Structure-function relationship and biogenesis regulation of the human telomerase holoenzyme

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 de novo 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.