title: Human cell senescence as a DNA damage response.
abstract: It has been established that telomere-dependent replicative senescence of human fibroblasts is stress-dependent. First, it was shown that telomere shortening, which is a major contributor to telomere uncapping, is stress-dependent to a significant degree. Second, the signalling pathway connecting telomere uncapping and replicative senescence appears to be the same as the one that is activated by DNA damage: uncapped telomeres activate signalling cascades involving the protein kinases ATM, ATR and, possibly, DNA-PK. Furthermore, phosphorylation of histone H2A.X facilitates the formation of DNA damage foci around uncapped telomeres, and this in turn activates downstream kinases Chk1 and Chk2 and, eventually, p53. It appears that this signalling pathway has to be maintained in order to keep cells in a senescent state. Thus, cellular senescence can be regarded as a permanently maintained DNA damage response state. This suggests that antibodies against DNA damage foci components might be useful markers for senescent cells in vivo.
authors.affiliation: Henry Wellcome Biogerontology Laboratory, Newcastle University, Newcastle upon Tyne NE4 6BE, UK. tvonzglinicki@ncl.ac.uk
authors.forename: T
authors.initials: T
authors.lastname: von Zglinicki
authors.forename: G
authors.initials: G
authors.lastname: Saretzki
authors.forename: J
authors.initials: J
authors.lastname: Ladhoff
authors.forename: F
authors.initials: F
authors.lastname: d'Adda di Fagagna
authors.forename: S P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016615:Telomere / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins