title: Five dysfunctional telomeres predict onset of senescence in human cells.
abstract: Replicative senescence is accompanied by a telomere-specific DNA damage response (DDR). We found that DDR+ telomeres occur spontaneously in early-passage normal human cells and increase in number with increasing cumulative cell divisions. DDR+ telomeres at replicative senescence retain TRF2 and RAP1 proteins, are not associated with end-to-end fusions and mostly result from strand-independent, postreplicative dysfunction. On the basis of the calculated number of DDR+ telomeres in G1-phase cells just before senescence and after bypassing senescence by inactivation of wild-type p53 function, we conclude that the accrual of five telomeres in G1 that are DDR+ but nonfusogenic is associated with p53-dependent senescence.
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, New South Wales 2145, Australia.
authors.forename: Zeenia
authors.initials: Z
authors.lastname: Kaul
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Cesare
authors.forename: Lily I
authors.initials: LI
authors.lastname: Huschtscha
authors.forename: Axel A
authors.initials: AA
authors.lastname: Neumann
authors.forename: Roger R
authors.initials: RR
authors.lastname: Reddel
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D006801:Humans; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis