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An Activity Switch in Human Telomerase Based on RNA Conformation and Shaped by TCAB1
An Activity Switch in Human Telomerase Based on RNA Conformation and Shaped by TCAB1
- Source :
- Cell. 174(1)
- Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Telomerase
RNA, Untranslated
Biology
General Biochemistry, Genetics and Molecular Biology
Article
Catalysis
Cell Line
Turn (biochemistry)
03 medical and health sciences
Humans
Progenitor cell
RNA, Small Interfering
Ribonucleoprotein
chemistry.chemical_classification
RNA Conformation
RNA
Nuclear Proteins
Telomere
Cell biology
030104 developmental biology
Enzyme
chemistry
Biocatalysis
Nucleic Acid Conformation
RNA Interference
HeLa Cells
Molecular Chaperones
Protein Binding
Subjects
Details
- ISSN :
- 10974172
- Volume :
- 174
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cell
- Accession number :
- edsair.doi.dedup.....7b34343cb09fba502ad2fea13547ae24