Pharmaceutical Sciences Faculty Publications

Title

Proteostatic Control of Telomerase Function Through TRiC-Mediated Folding of TCAB1

Document Type

Article

Publication Date

12-4-2014

Journal Title

Cell

ISSN

1097-4172

Volume

159

Issue

6

First Page

1389

Last Page

1403

DOI

10.1016/j.cell.2014.10.059

PubMed ID

25467444

Abstract

Telomere maintenance by telomerase is impaired in the stem cell disease dyskeratosis congenita and during human aging. Telomerase depends upon a complex pathway for enzyme assembly, localization in Cajal bodies, and association with telomeres. Here, we identify the chaperonin CCT/TRiC as a critical regulator of telomerase trafficking using a high-content genome-wide siRNA screen in human cells for factors required for Cajal body localization. We find that TRiC is required for folding the telomerase cofactor TCAB1, which controls trafficking of telomerase and small Cajal body RNAs (scaRNAs). Depletion of TRiC causes loss of TCAB1 protein, mislocalization of telomerase and scaRNAs to nucleoli, and failure of telomere elongation. DC patient-derived mutations in TCAB1 impair folding by TRiC, disrupting telomerase function and leading to severe disease. Our findings establish a critical role for TRiC-mediated protein folding in the telomerase pathway and link proteostasis, telomere maintenance, and human disease.

Keywords

Chaperonin, TCP-1, fluorescence, protein folding, telomerase, telomere

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