Pharmaceutical Sciences Faculty Publications
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
Recommended Citation
Freund, Adam; Zhong, Franklin L.; Venteicher, Andrew S.; Meng, Zhaojing; Veenstra, Timothy D.; Frydman, Judith; and Artandi, Steven E., "Proteostatic Control of Telomerase Function Through TRiC-Mediated Folding of TCAB1" (2014). Pharmaceutical Sciences Faculty Publications. 180.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/180