PMID:14608368

Citation	d'Adda di Fagagna, F, Reaper, PM, Clay-Farrace, L, Fiegler, H, Carr, P, Von Zglinicki, T, Saretzki, G, Carter, NP and Jackson, SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194-8
Abstract	Most human somatic cells can undergo only a limited number of population doublings in vitro. This exhaustion of proliferative potential, called senescence, can be triggered when telomeres--the ends of linear chromosomes-cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. Finally, we show that inactivation of DNA damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.
Links	PubMed Online version:10.1038/nature02118
Keywords	Carrier Proteins/metabolism; Cell Aging; Cell Cycle; Cell Cycle Proteins/metabolism; Checkpoint Kinase 2; Chromatin/metabolism; DNA Damage; DNA Repair; DNA-Binding Proteins/metabolism; Fibroblasts/cytology; Fibroblasts/metabolism; Histones/metabolism; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins/metabolism; Phosphoproteins; Phosphorylation; Protein Binding; Protein Kinases/metabolism; Protein-Serine-Threonine Kinases; S Phase; Telomere/metabolism; Telomere/pathology; Trans-Activators/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:CHK2		GO:0042127: regulation of cell proliferation	ECO:0000314:		P		Figure 1.n. shows that phosphorylation at threonine 68 is upregulated in senescent cells compared to proliferating cells	complete CACAO 9425
HUMAN:CHK1		GO:0042127: regulation of cell proliferation	ECO:0000314:		P		Figure 1. (m) This protein, which has been shown to be involved with DNA damage checkpoint processes, has also been found in higher abundance in senescent cells. A Western blot obtained from whole-cell extracts was used to compare Chk1 abundance of senescent cells to proliferating cells to telomerized proliferating cells to irradiated proliferating cells. The results showed that Chk1 expression in senescent cells was greater than all other groups, except irradiated proliferating cells which were used to represent cells with double stranded DNA breaks.	complete
HUMAN:CHK1		GO:0042127:	ECO:0000314:				Figure 1.m. shows that phosphorylation at serine 345 is upregulated in senescent cells compared to proliferating cells.	complete CACAO 9426
HUMAN:SMC1A		GO:0042127: regulation of cell proliferation	ECO:0000314:		P		Fig 1 (k) shows that phosphorylation of serine 966 is upregulated in senescent cells compared to proliferating cells.	complete CACAO 9428
HUMAN:RAD17		GO:0042127: regulation of cell proliferation	ECO:0000314:		P		Figure 1 L shows that phosphorylation at serine 645 is conserved among senescent cells, late population doubling cells, and undamaged proliferating cells.	complete CACAO 9430

References

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