Defining the telomerase holoenzyme in progenitor cells with aging

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): Identification of a definitive cause for mammalian aging has remained elusive despite decades of investigation. Many processes have been found to be altered in aged organisms, including telomere maintenance, insulin signaling, mitochondrial function, DNA repair, and proteostasis, among others. How these processes are connected remains incompletely understood. We have established a new genetic and biochemical connection between two of these critical aging associated processes - telomere maintenance and proteostasis. Telomeres shorten during human aging in diverse tissues and the reason that telomeres cannot be efficiently maintained in somatic tissues with advancing age is not known. We have shown that telomere maintenance in human cells and in human tissues is exquisitely dependent upon the action of the chaperonin TRiC. During evolution of higher eukaryotes, telomerase hijacked a small nuclear RNA pathway, required for telomerase assembly and trafficking. TCAB1 is a telomerase holoenzyme protein and the protein factor that enables trafficking of both telomerase and small Cajal body RNAs (scaRNAs) to Cajal bodies. Human germline mutations in TCAB1 cause the premature aging and stem cell disease dyskeratosis congenita. We have shown that telomerase requires TCAB1 for proper trafficking within the nucleus and for telomere maintenance. TCAB1 serves a less well understood role in enabling scaRNAs to support post-transcriptional modification of splicing RNAs - and presumably in splicing and maturation of cellular pre-mRNAs. Through a genetic screen in human cells, we recently discovered that TCAB1 is an obligate substrate of TRiC. If TRiC mediated folding of TCAB1 is disrupted, telomerase function is abrogated, tissue maintenance is disrupted and dyskeratosis congenita ensues. This novel connection between proteostasis and telomere maintenance raises important question regarding the cause of telomere shortening with advancing age, but also how proteostasis may connect more broadly to RNA-dependent processes. We propose that impaired TRiC function with aging may lead to misfolded TCAB1, in turn causing both diminished telomerase function and altered mRNA splicing. This hypothesis suggests that reduced proteostasis may propagate broadly to RNA networks. The goals of this proposal are: (1) To understand how telomerase catalytic function depends upon TCAB1 (2) To determine how TCAB1 loss affects scaRNA function and RNA splicing and (3) To determine how TCAB1 loss affects tissue homeostasis.