TY - JOUR
T1 - Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1
AU - Freund, Adam
AU - Zhong, Franklin L.
AU - Venteicher, Andrew S.
AU - Meng, Zhaojing
AU - Veenstra, Timothy D.
AU - Frydman, Judith
AU - Artandi, Steven E.
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/12/4
Y1 - 2014/12/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.10.059
DO - 10.1016/j.cell.2014.10.059
M3 - Article
C2 - 25467444
AN - SCOPUS:84923591348
SN - 0092-8674
VL - 159
SP - 1389
EP - 1403
JO - Cell
JF - Cell
IS - 6
ER -