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Title: Cryo-EM structure of substrate-bound human telomerase holoenzyme

Abstract

Telomerase adds telomeric repeats to chromosome ends to balance incomplete replication. Telomerase regulation is implicated in cancer, aging and other human diseases, but progress towards telomerase clinical manipulation is hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of substrate-bound human telomerase holoenzyme at subnanometer resolution, describing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein-RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics

Authors:
 [1];  [2];  [3];  [1];  [2];  [1];  [2]
  1. Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Univ. of California, Berkeley, CA (United States)
  3. Univ. of California, Berkeley, CA (United States); Harvard Medical School, Boston, MA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1492320
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 557; Journal Issue: 7704; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Nguyen, Thi Hoang Duong, Tam, Jane, Wu, Robert A., Greber, Basil J., Toso, Daniel, Nogales, Eva, and Collins, Kathleen. Cryo-EM structure of substrate-bound human telomerase holoenzyme. United States: N. p., 2018. Web. doi:10.1038/s41586-018-0062-x.
Nguyen, Thi Hoang Duong, Tam, Jane, Wu, Robert A., Greber, Basil J., Toso, Daniel, Nogales, Eva, & Collins, Kathleen. Cryo-EM structure of substrate-bound human telomerase holoenzyme. United States. doi:10.1038/s41586-018-0062-x.
Nguyen, Thi Hoang Duong, Tam, Jane, Wu, Robert A., Greber, Basil J., Toso, Daniel, Nogales, Eva, and Collins, Kathleen. Wed . "Cryo-EM structure of substrate-bound human telomerase holoenzyme". United States. doi:10.1038/s41586-018-0062-x. https://www.osti.gov/servlets/purl/1492320.
@article{osti_1492320,
title = {Cryo-EM structure of substrate-bound human telomerase holoenzyme},
author = {Nguyen, Thi Hoang Duong and Tam, Jane and Wu, Robert A. and Greber, Basil J. and Toso, Daniel and Nogales, Eva and Collins, Kathleen},
abstractNote = {Telomerase adds telomeric repeats to chromosome ends to balance incomplete replication. Telomerase regulation is implicated in cancer, aging and other human diseases, but progress towards telomerase clinical manipulation is hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of substrate-bound human telomerase holoenzyme at subnanometer resolution, describing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein-RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics},
doi = {10.1038/s41586-018-0062-x},
journal = {Nature (London)},
number = 7704,
volume = 557,
place = {United States},
year = {2018},
month = {4}
}

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Works referenced in this record:

RELION: Implementation of a Bayesian approach to cryo-EM structure determination
journal, December 2012