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Telomere Length Dynamics and the Evolution of Cancer Genome Architecture
Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that b...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855704/ https://www.ncbi.nlm.nih.gov/pubmed/29415479 http://dx.doi.org/10.3390/ijms19020482 |
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author | Cleal, Kez Norris, Kevin Baird, Duncan |
author_facet | Cleal, Kez Norris, Kevin Baird, Duncan |
author_sort | Cleal, Kez |
collection | PubMed |
description | Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage–fusion–bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements. |
format | Online Article Text |
id | pubmed-5855704 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-58557042018-03-20 Telomere Length Dynamics and the Evolution of Cancer Genome Architecture Cleal, Kez Norris, Kevin Baird, Duncan Int J Mol Sci Review Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage–fusion–bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements. MDPI 2018-02-06 /pmc/articles/PMC5855704/ /pubmed/29415479 http://dx.doi.org/10.3390/ijms19020482 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Cleal, Kez Norris, Kevin Baird, Duncan Telomere Length Dynamics and the Evolution of Cancer Genome Architecture |
title | Telomere Length Dynamics and the Evolution of Cancer Genome Architecture |
title_full | Telomere Length Dynamics and the Evolution of Cancer Genome Architecture |
title_fullStr | Telomere Length Dynamics and the Evolution of Cancer Genome Architecture |
title_full_unstemmed | Telomere Length Dynamics and the Evolution of Cancer Genome Architecture |
title_short | Telomere Length Dynamics and the Evolution of Cancer Genome Architecture |
title_sort | telomere length dynamics and the evolution of cancer genome architecture |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855704/ https://www.ncbi.nlm.nih.gov/pubmed/29415479 http://dx.doi.org/10.3390/ijms19020482 |
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