title: Length-dependent processing of telomeres in the absence of telomerase.
abstract: In the absence of telomerase, telomeres progressively shorten with every round of DNA replication, leading to replicative senescence. In telomerase-deficient Saccharomyces cerevisiae, the shortest telomere triggers the onset of senescence by activating the DNA damage checkpoint and recruiting homologous recombination (HR) factors. Yet, the molecular structures that trigger this checkpoint and the mechanisms of repair have remained elusive. By tracking individual telomeres, we show that telomeres are subjected to different pathways depending on their length. We first demonstrate a progressive accumulation of subtelomeric single-stranded DNA (ssDNA) through 5'-3' resection as telomeres shorten. Thus, exposure of subtelomeric ssDNA could be the signal for cell cycle arrest in senescence. Strikingly, early after loss of telomerase, HR counteracts subtelomeric ssDNA accumulation rather than elongates telomeres. We then asked whether replication repair pathways contribute to this mechanism. We uncovered that Rad5, a DNA helicase/Ubiquitin ligase of the error-free branch of the DNA damage tolerance (DDT) pathway, associates with native telomeres and cooperates with HR in senescent cells. We propose that DDT acts in a length-independent manner, whereas an HR-based repair using the sister chromatid as a template buffers precocious 5'-3' resection at the shortest telomeres.
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, FRE3354, 75005 Paris, France, Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Université de Lyon 1, UMR5239, 69364 Lyon Cedex 07, France, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice F-06107, France and Department of Medical Genetics, CHU Nice, 06202 Nice cedex 3, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Fallet
authors.forename: Pascale
authors.initials: P
authors.lastname: Jolivet
authors.forename: Julien
authors.initials: J
authors.lastname: Soudet
authors.forename: Michael
authors.initials: M
authors.lastname: Lisby
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Teixeira
mesh_terms: D004265:DNA Helicases / Q000032:analysis; D004277:DNA, Single-Stranded / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D016195:G2 Phase / Q000235:genetics; D053484:RecQ Helicases / Q000378:metabolism; D059767:Recombinational DNA Repair; D016196:S Phase / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000032:analysis / Q000378:metabolism; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000737:chemistry; D059505:Telomere Homeostasis; D059506:Telomere Shortening
chemical_list: D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D019098:Telomerase; D004720:Endonucleases; C411624:MUS81 protein, S cerevisiae; C076225:RAD5 protein, S cerevisiae; C090472:SGS1 protein, S cerevisiae; D004265:DNA Helicases; D053484:RecQ Helicases