Telomerase RNP: from core RNA structure to the short-telomere senescence response
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Date
2015-10-21
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Johns Hopkins University
Abstract
Telomerase is a ribonucleoprotein that extends the ends of linear chromosomes. The RNA component contributes to many important functions of the enzyme including providing the template for reverse transcription by TERT, presenting a flexible scaffold for accessory subunit binding and contributing to enzyme coordination during catalysis through a poorly understood mechanism. Despite these crucial roles, the structure-function relationships of the RNA have remained undefined due, in part, to the lack of detailed structural information available. Here I present refined secondary-structure models for the central cores of both the human and yeast RNA, highlighting conserved regions of flexibility adjacent to the template that likely play a role in enzyme catalysis. I also show that disease-associated mutations in telomerase RNA alter the folding equilibrium to a degree that is likely sufficient to disrupt enzyme activity. Telomerase function is critical for maintaining genome stability within the cell. When telomerase is absent or has compromised function the result is progressive telomere shortening until a specific cell-cycle arrest known as senescence. The adaptive changes undergone by the cell during this process remain unclear. Using RNA-seq I have shown that senescence is a distinct state both phenotypically and transcriptionally, although it overlaps substantially with other related conditions such as slow growth and the DNA damage response. The senescence response is consistent with many pro-survival adaptations, including initiation of a starvation response and concurrent upregulation of autophagy. These findings place senescence within a wider context of other stress responses, while also highlighting the unique challenges faced by cells having to deal with progressively shortening telomeres.
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Keywords
Telomerase RNA, Senescence