title: Defective DNA single-strand break repair is responsible for senescence and neoplastic escape of epithelial cells.
abstract: The main characteristic of senescence is its stability which relies on the persistence of DNA damage. We show that unlike fibroblasts, senescent epithelial cells do not activate an ATM-or ATR-dependent DNA damage response (DDR), but accumulate oxidative-stress-induced DNA single-strand breaks (SSBs). These breaks remain unrepaired because of a decrease in PARP1 expression and activity. This leads to the formation of abnormally large and persistent XRCC1 foci that engage a signalling cascade involving the p38MAPK and leading to p16 upregulation and cell cycle arrest. Importantly, the default in SSB repair also leads to the emergence of post-senescent transformed and mutated precancerous cells. In human-aged skin, XRCC1 foci accumulate in the epidermal cells in correlation with a decline of PARP1, whereas DDR foci accumulate mainly in dermal fibroblasts. These findings point SSBs as a DNA damage encountered by epithelial cells with aging which could fuel the very first steps of carcinogenesis.
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Joe
authors.initials: J
authors.lastname: Nassour
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Martien
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Martin
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Emeric
authors.initials: E
authors.lastname: Deruy
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tomellini
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Malaquin
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bouali
authors.affiliation: Commissariat à l'Energie Atomique (CEA), Laboratoire de Radiobiologie et Oncologie (LRO), 18 route du Panorama - BP6, 92265 Fontenay-aux-Roses 53011, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Sabatier
authors.affiliation: Institute of Pathology, University of Bonn, 53011 Bonn, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wernert
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.|Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, CNRS, UMR7284, INSERM U108, Faculty of Medecine of Nice; CHU of Nice, Nice, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pinte
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, CNRS, UMR7284, INSERM U108, Faculty of Medecine of Nice; CHU of Nice, Nice, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Albin
authors.initials: A
authors.lastname: Pourtier
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pluquet
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Abbadie
mesh_terms: D016922:Cellular Senescence; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
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