DNA damage checkpoint kinase Chk2 triggers replicative senescence
Language: 
English
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 gamma-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. gamma-H2AX (though not Chk2) was shown to associate directly with telomeric DNA. Furthermore, inactivation of Chk2 in human fibroblasts led to a fall in p21(waf1) 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.

Author(s): 
Gire, VÈronique
Roux, Pierre
Wynford-Thomas, David
Brondello, Jean-Marc
Dulic, Vjekoslav
Item Type: 
Journal Article
Publication Title: 
The EMBO journal
Journal Abbreviation: 
EMBO J.
Publication Date: 
7/7/2004
Publication Year: 
2004
Pages: 
2554-2563
Volume: 
23
Issue: 
13
ISSN: 
0261-4189
DOI: 
10.1038/sj.emboj.7600259
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 15192702 PMCID: PMC449769

Turabian/Chicago Citation

VÈronique Gire, Pierre Roux, David Wynford-Thomas, Jean-Marc Brondello and Vjekoslav Dulic. 7/7/2004. "DNA damage checkpoint kinase Chk2 triggers replicative senescence." The EMBO journal 23: 13: 2554-2563. 10.1038/sj.emboj.7600259.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1038/sj.emboj.7600259 | issn = 0261-4189 | volume = 23 | pages = 2554-2563 | last = Gire | first = VÈronique | coauthors = Roux, Pierre, Wynford-Thomas, David, Brondello, Jean-Marc, Dulic, Vjekoslav | title = DNA damage checkpoint kinase Chk2 triggers replicative senescence | journal = The EMBO journal | date = 7/7/2004 | pmid = | pmc = }} </ref>