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Nat Commun. 2016 Jan 29;7:10399. doi: 10.1038/ncomms10399.

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

Author information

Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
Commissariat à l'Energie Atomique (CEA), Laboratoire de Radiobiologie et Oncologie (LRO), 18 route du Panorama - BP6, 92265 Fontenay-aux-Roses 53011, France.
Institute of Pathology, University of Bonn, 53011 Bonn, Germany.
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.


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.

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