title: Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response.
abstract: Telomeres cap the ends of chromosomes and regulate the replicative life span of human somatic cells. Telomere function is lost upon critical shortening and a p53-dependent checkpoint that detects altered telomere states at the G1/S transition was proposed to act as a regulator of the telomere damage response. We show that telomerase-negative human fibroblasts spend more time in G2 phase as they approach senescence and this delay is associated with manifestations of telomere dysfunction and the triggering of an ATM/ATR-dependent DNA damage signal. This correlates with a partial release of telomeric proteins TRF1 and TRF2. Analysis of the consequences of TRF1 and TRF2 depletion or over-expression of mutated versions revealed that telomere uncapping or telomere replication stress also led to DNA damage signalling in G2. Progression through mitosis of these cells was associated with signs of incomplete telomere terminal processing. We also observed an increase in sister chromatid-type telomere aberrations in senescing fibroblasts indicating that defects of telomere post-replicative events increased as cells age. Our results link a post-replicative damage response at eroded telomeres to G2 arrest signalling and challenge the current paradigm that the checkpoint response to short telomeres occurs primarily at the G1/S transition in human cells.
authors.affiliation: Universités Montpellier 2 et 1, CRBM-CNRS UMR 5237, 1919, route de Mende, 34293 Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Jullien
authors.forename: Marie
authors.initials: M
authors.lastname: Mestre
authors.forename: Pierre
authors.initials: P
authors.lastname: Roux
authors.forename: Véronique
authors.initials: V
authors.lastname: Gire
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016195:G2 Phase; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D006801:Humans; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D059506:Telomere Shortening; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases