Stn1 is critical for telomere maintenance and long-term viability of somatic human cells

Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regul...

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Main Authors:	Boccardi, Virginia, Razdan, Neetu, Kaplunov, Jessica, Mundra, Jyoti J, Kimura, Masayuki, Aviv, Abraham, Herbig, Utz
Format:	Online
Language:	English
Published:	BlackWell Publishing Ltd 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406666/

id	pubmed-4406666
recordtype	oai_dc
spelling	pubmed-44066662015-06-01 Stn1 is critical for telomere maintenance and long-term viability of somatic human cells Boccardi, Virginia Razdan, Neetu Kaplunov, Jessica Mundra, Jyoti J Kimura, Masayuki Aviv, Abraham Herbig, Utz Original Articles Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells. BlackWell Publishing Ltd 2015-06 2015-02-14 /pmc/articles/PMC4406666/ /pubmed/25684230 http://dx.doi.org/10.1111/acel.12289 Text en © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Boccardi, Virginia Razdan, Neetu Kaplunov, Jessica Mundra, Jyoti J Kimura, Masayuki Aviv, Abraham Herbig, Utz
spellingShingle	Boccardi, Virginia Razdan, Neetu Kaplunov, Jessica Mundra, Jyoti J Kimura, Masayuki Aviv, Abraham Herbig, Utz Stn1 is critical for telomere maintenance and long-term viability of somatic human cells
author_facet	Boccardi, Virginia Razdan, Neetu Kaplunov, Jessica Mundra, Jyoti J Kimura, Masayuki Aviv, Abraham Herbig, Utz
author_sort	Boccardi, Virginia
title	Stn1 is critical for telomere maintenance and long-term viability of somatic human cells
title_short	Stn1 is critical for telomere maintenance and long-term viability of somatic human cells
title_full	Stn1 is critical for telomere maintenance and long-term viability of somatic human cells
title_fullStr	Stn1 is critical for telomere maintenance and long-term viability of somatic human cells
title_full_unstemmed	Stn1 is critical for telomere maintenance and long-term viability of somatic human cells
title_sort	stn1 is critical for telomere maintenance and long-term viability of somatic human cells
description	Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells.
publisher	BlackWell Publishing Ltd
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406666/
_version_	1613214584659771392

Stn1 is critical for telomere maintenance and long-term viability of somatic human cells

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