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DNA damage checkpoint kinase Chk2 triggers replicative senescence

Gire, Véronique, Roux, Pierre, Wynford-Thomas, David, Brondello, Jean-Marc and Dulic, Vjekoslav 2004. DNA damage checkpoint kinase Chk2 triggers replicative senescence. The EMBO journal 23 (13) , pp. 2554-2563. 10.1038/sj.emboj.7600259

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Abstract

Telomere shortening in normal human cells causes replicative senescence, a p53-dependent growth arrest state, which is thought to represent an innate defence against tumour progression. However, although it has been postulated that critical telomere loss generates a 'DNA damage' signal, the signalling pathway(s) that alerts cells to short dysfunctional telomeres remains only partially defined. We show that senescence in human fibroblasts is associated with focal accumulation of -H2AX and phosphorylation of Chk2, known mediators of the ataxia-telangiectasia mutated regulated signalling pathway activated by DNA double-strand breaks. Both these responses increased in cells grown beyond senescence through inactivation of p53 and pRb, indicating that they are driven by continued cell division and not a consequence of senescence. -H2AX (though not Chk2) was shown to associate directly with telomeric DNA. Furthermore, inactivation of Chk2 in human fibroblasts led to a fall in p21waf1 expression and an extension of proliferative lifespan, consistent with failure to activate p53. Thus, Chk2 forms an essential component of a common pathway signalling cell cycle arrest in response to both telomere erosion and DNA damage.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: Chk2 ; DNA double-strand breaks ; -H2AX ; Senescence ; Telomeres
Publisher: Nature Publishing Group for the European Molecular Biology Organization
ISSN: 14602075
Related URLs:
Last Modified: 19 Mar 2016 22:00
URI: https://orca.cardiff.ac.uk/id/eprint/163

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