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Cell cycle arrest in replicative senescence is not an immediate consequence of telomere dysfunction.

Shamim Nassrally, M; Lau, A; Wise, K; John, N; Kotecha, S; Lee, KL; Brooks, RF (2019) Cell cycle arrest in replicative senescence is not an immediate consequence of telomere dysfunction. Mech Ageing Dev, 179. pp. 11-22. ISSN 1872-6216 https://doi.org/10.1016/j.mad.2019.01.009
SGUL Authors: Brooks, Robert Frederick

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Abstract

In replicative senescence, cells with critically-short telomeres activate a DNA-damage response leading to cell-cycle arrest, while those without telomere dysfunction would be expected to cycle normally. However, population growth declines more gradually than such a simple binary switch between cycling and non-cycling states would predict. We show here that late-passage cultures of human fibroblasts are not a simple mixture of cycling and non-cycling cells. Rather, although some cells had short cycle times comparable to those of younger cells, others continued to divide but with greatly extended cycle times, indicating a more-gradual approach to permanent arrest. Remarkably, in late passage cells, the majority showed prominent DNA-damage foci positive for 53BP1, yet many continued to divide. Evidently, the DNA-damage-response elicited by critically-short telomeres is not initially strong enough for complete cell-cycle arrest. A similar continuation of the cell cycle in the face of an active DNA-damage response was also seen in cells treated with a low dose of doxorubicin sufficient to produce multiple 53BP1 foci in all nuclei. Cell cycle checkpoint engagement in response to DNA damage is thus weaker than generally supposed, explaining why an accumulation of dysfunctional telomeres is needed before marked cell cycle elongation or permanent arrest is achieved.

Item Type: Article
Additional Information: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: 53BP1, Cell senescence, DNA-damage response, clonal heterogeneity, telomere-dysfunction, 1103 Clinical Sciences, Gerontology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Mech Ageing Dev
ISSN: 1872-6216
Language: eng
Dates:
DateEvent
April 2019Published
30 January 2019Published Online
28 January 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
PubMed ID: 30710559
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110627
Publisher's version: https://doi.org/10.1016/j.mad.2019.01.009

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