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TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity

TIN2 is an important regulator of telomere length, and mutations in TINF2, the gene encoding TIN2, cause short-telomere syndromes. While the genetics underscore the importance of TIN2, the mechanism through which TIN2 regulates telomere length remains unclear. Here, we tested the effects of human TI...

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Autores principales: Pike, Alexandra M., Strong, Margaret A., Ouyang, John Paul T., Greider, Carol W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791651/
https://www.ncbi.nlm.nih.gov/pubmed/31383750
http://dx.doi.org/10.1128/MCB.00593-18
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author Pike, Alexandra M.
Strong, Margaret A.
Ouyang, John Paul T.
Greider, Carol W.
author_facet Pike, Alexandra M.
Strong, Margaret A.
Ouyang, John Paul T.
Greider, Carol W.
author_sort Pike, Alexandra M.
collection PubMed
description TIN2 is an important regulator of telomere length, and mutations in TINF2, the gene encoding TIN2, cause short-telomere syndromes. While the genetics underscore the importance of TIN2, the mechanism through which TIN2 regulates telomere length remains unclear. Here, we tested the effects of human TIN2 on telomerase activity. We identified a new isoform in human cells, TIN2M, that is expressed at levels similar to those of previously studied TIN2 isoforms. All three TIN2 isoforms localized to and maintained telomere integrity in vivo, and localization was not disrupted by telomere syndrome mutations. Using direct telomerase activity assays, we discovered that TIN2 stimulated telomerase processivity in vitro. All of the TIN2 isoforms stimulated telomerase to similar extents. Mutations in the TPP1 TEL patch abrogated this stimulation, suggesting that TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. We conclude from our data and previously published work that TIN2/TPP1/POT1 is a functional shelterin subcomplex.
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spelling pubmed-67916512019-10-21 TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity Pike, Alexandra M. Strong, Margaret A. Ouyang, John Paul T. Greider, Carol W. Mol Cell Biol Research Article TIN2 is an important regulator of telomere length, and mutations in TINF2, the gene encoding TIN2, cause short-telomere syndromes. While the genetics underscore the importance of TIN2, the mechanism through which TIN2 regulates telomere length remains unclear. Here, we tested the effects of human TIN2 on telomerase activity. We identified a new isoform in human cells, TIN2M, that is expressed at levels similar to those of previously studied TIN2 isoforms. All three TIN2 isoforms localized to and maintained telomere integrity in vivo, and localization was not disrupted by telomere syndrome mutations. Using direct telomerase activity assays, we discovered that TIN2 stimulated telomerase processivity in vitro. All of the TIN2 isoforms stimulated telomerase to similar extents. Mutations in the TPP1 TEL patch abrogated this stimulation, suggesting that TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. We conclude from our data and previously published work that TIN2/TPP1/POT1 is a functional shelterin subcomplex. American Society for Microbiology 2019-10-11 /pmc/articles/PMC6791651/ /pubmed/31383750 http://dx.doi.org/10.1128/MCB.00593-18 Text en Copyright © 2019 Pike et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Pike, Alexandra M.
Strong, Margaret A.
Ouyang, John Paul T.
Greider, Carol W.
TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity
title TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity
title_full TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity
title_fullStr TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity
title_full_unstemmed TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity
title_short TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity
title_sort tin2 functions with tpp1/pot1 to stimulate telomerase processivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791651/
https://www.ncbi.nlm.nih.gov/pubmed/31383750
http://dx.doi.org/10.1128/MCB.00593-18
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