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Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms

Davis, Terence ORCID:, Singhrao, Simarjit Kaur, Wyllie, Fiona Sandra, Haughton, Michele Fleur, Smith, Paul James, Wiltshire, Marie, Wynford-Thomas, David, Jones, Christopher John, Faragher, Richard G. A. and Kipling, David Glyn 2003. Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms. Journal of Cell Science (JCS) 116 (7) , pp. 1349-57. 10.1242/jcs.00331

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Werner-syndrome fibroblasts have a reduced in vitro life span before entering replicative senescence. Although this has been thought to be causal in the accelerated ageing of this disease, controversy remains as to whether Werner syndrome is showing the acceleration of a normal cellular ageing mechanism or the occurrence of a novel Werner-syndrome-specific process. Here, we analyse the signalling pathways responsible for senescence in Werner-syndrome fibroblasts. Cultured Werner-syndrome (AG05229) fibroblasts senesced after approximately 20 population doublings with most of the cells having a 2N content of DNA. This was associated with hypophosphorylated pRb and high levels of p16(Ink4a) and p21(Waf1). Senescent AG05229 cells re-entered the cell cycle following microinjection of a p53-neutralizing antibody. Similarly, production of the human papilloma virus 16 E6 oncoprotein in presenescent AG05229 cells resulted in senescence being bypassed and extended cellular life span. Werner-syndrome fibroblasts expressing E6 did not proliferate indefinitely but reached a second proliferative lifespan barrier, termed M(int), that could be bypassed by forced production of telomerase in post-M1 E6-producing cells. The conclusions from these studies are that: (1) replicative senescence in Werner-syndrome fibroblasts is a telomere-induced p53-dependent event; and (2) the intermediate lifespan barrier M(int) is also a telomere-induced event, although it appears to be independent of p53. Werner-syndrome fibroblasts resemble normal human fibroblasts for both these proliferative lifespan barriers, with the strong similarity between the signalling pathway linking telomeres to cell-cycle arrest in Werner-syndrome and normal fibroblasts providing further support for the defect in Werner syndrome causing the acceleration of a normal ageing mechanism.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: Ageing ; Cellular senescence ; Oncoprotein ; Microinjection ; Telomerase
Publisher: Company of Biologists
ISSN: 1477-9137
Last Modified: 01 Nov 2023 07:35

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