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Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer

Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current repor...

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Autores principales: Kim, Wanil, Ludlow, Andrew T., Min, Jaewon, Robin, Jerome D., Stadler, Guido, Mender, Ilgen, Lai, Tsung-Po, Zhang, Ning, Wright, Woodring E., Shay, Jerry W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5169358/
https://www.ncbi.nlm.nih.gov/pubmed/27977688
http://dx.doi.org/10.1371/journal.pbio.2000016
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author Kim, Wanil
Ludlow, Andrew T.
Min, Jaewon
Robin, Jerome D.
Stadler, Guido
Mender, Ilgen
Lai, Tsung-Po
Zhang, Ning
Wright, Woodring E.
Shay, Jerry W.
author_facet Kim, Wanil
Ludlow, Andrew T.
Min, Jaewon
Robin, Jerome D.
Stadler, Guido
Mender, Ilgen
Lai, Tsung-Po
Zhang, Ning
Wright, Woodring E.
Shay, Jerry W.
author_sort Kim, Wanil
collection PubMed
description Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.
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spelling pubmed-51693582016-12-28 Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer Kim, Wanil Ludlow, Andrew T. Min, Jaewon Robin, Jerome D. Stadler, Guido Mender, Ilgen Lai, Tsung-Po Zhang, Ning Wright, Woodring E. Shay, Jerry W. PLoS Biol Research Article Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal. Public Library of Science 2016-12-15 /pmc/articles/PMC5169358/ /pubmed/27977688 http://dx.doi.org/10.1371/journal.pbio.2000016 Text en © 2016 Kim et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kim, Wanil
Ludlow, Andrew T.
Min, Jaewon
Robin, Jerome D.
Stadler, Guido
Mender, Ilgen
Lai, Tsung-Po
Zhang, Ning
Wright, Woodring E.
Shay, Jerry W.
Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer
title Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer
title_full Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer
title_fullStr Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer
title_full_unstemmed Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer
title_short Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer
title_sort regulation of the human telomerase gene tert by telomere position effect—over long distances (tpe-old): implications for aging and cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5169358/
https://www.ncbi.nlm.nih.gov/pubmed/27977688
http://dx.doi.org/10.1371/journal.pbio.2000016
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