Defective DNA single-strand break repair is responsible for senescence and neoplastic escape of epithelial cells

Joe Nassour, Sébastien Martien, Nathalie Martin, Emeric Deruy, Elisa Tomellini, Nicolas Malaquin, Fatima Bouali, Laure Sabatier, Nicolas Wernert, Sébastien Pinte, Eric Gilson, Albin Pourtier, Olivier Pluquet and Corinne Abbadie ()
Additional contact information
Joe Nassour: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Sébastien Martien: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Nathalie Martin: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Emeric Deruy: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Elisa Tomellini: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Nicolas Malaquin: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Fatima Bouali: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Laure Sabatier: Commissariat à l'Energie Atomique (CEA), Laboratoire de Radiobiologie et Oncologie (LRO), 18 route du Panorama - BP6
Nicolas Wernert: Institute of Pathology, University of Bonn
Sébastien Pinte: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Eric Gilson: 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
Albin Pourtier: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Olivier Pluquet: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies
Corinne Abbadie: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10399

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