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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We thank members of the Artandi and Frydman labs for helpful discussions and advice. We thank David Solow-Cordero in the Stanford High-Throughput Bioscience Center, with support from NIH NCRR Instrumentation grant S10RR026338. We are grateful to Anthony Tomlinson for generously providing purified bovine TRiC and to Sharon Savage for supplying DC patient lymphoblasts. A.F. was supported by Stanford Cancer Biology Training Program (T32 CA09302) and by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. F.L.Z. was supported by a fellowship from the Agency for Science, Technology, and Research (A ∗ STAR), Singapore. This work was supported by NIH grants AG033747, CA125453, CA111691, and AG036695 and by the Glenn Foundation for Medical Research.