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Cell v.174 no.1, 2018년, pp.218 - 230.e13   SCI SCIE
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An Activity Switch in Human Telomerase Based on RNA Conformation and Shaped by TCAB1

Chen, Lu (Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Roake, Caitlin M. (Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Freund, Adam (Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Batista, Pedro J. (Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Tian, Siqi (Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Yin, Yi A. (Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Gajera, Chandresh R. (Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Lin, Shengda (Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Lee, Byron (Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Pech, Matthew F. (Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA ) ; Venteicher, Andrew S. ; Das, Rhiju ; Chang, Howard Y. ; Artandi, Steven E. ;
  • 초록  

    Summary Ribonucleoprotein enzymes require dynamic conformations of their RNA constituents for regulated catalysis. Human telomerase employs a non-coding RNA (hTR) with a bipartite arrangement of domains—a template-containing core and a distal three-way junction (CR4/5) that stimulates catalysis through unknown means. Here, we show that telomerase activity unexpectedly depends upon the holoenzyme protein TCAB1, which in turn controls conformation of CR4/5. Cells lacking TCAB1 exhibit a marked reduction in telomerase catalysis without affecting enzyme assembly. Instead, TCAB1 inactivation causes unfolding of CR4/5 helices that are required for catalysis and for association with the telomerase reverse-transcriptase (TERT). CR4/5 mutations derived from patients with telomere biology disorders provoke defects in catalysis and TERT binding similar to TCAB1 inactivation. These findings reveal a conformational “activity switch” in human telomerase RNA controlling catalysis and TERT engagement. The identification of two discrete catalytic states for telomerase suggests an intramolecular means for controlling telomerase in cancers and progenitor cells. Highlights Telomerase catalytic activity is reduced in the absence of TCAB1 TCAB1 directly stimulates catalytic activity of the assembled telomerase complex TCAB1 controls folding of CR4/5, a distal domain in the telomerase RNA component An RNA activity switch in telomerase toggled by TCAB1 controls telomerase activity Graphical Abstract [DISPLAY OMISSION]


  • 주제어

    telomerase .   telomere .   TCAB1 .   icSHAPE .   CR4/5 .   CAB box .   H/ACA RNP .   RNA folding .   Cajal body .   dyskeratosis congenital.  

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