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.

Effects of age on the frequency of micronuclei and degenerative nuclear abnormalities

“…During the aging process, the enzymes involved in DNA repair become less and less common, which increases the susceptibility of cells to genotoxic agents. 31,32 Kirsch-Volders et al 33 suggested that flaws in the cellular defense systems that protect against DNA damage, as well as the reduced efficiency of DNA repair, can lead to an accumulation of mutations. These mutations, either in isolation or in combination with other age-related alterations, can contribute to aging and the development of age-related illnesses.…”

A novel role for DNA single-strand breaks in senescence and neoplastic escape of epithelial cells

“…Conversely, sustained antioxidant treatment was sufficient to reduce the SSB level, delay senescence, and suppress post-senescence emergence. 2 In conclusion, we describe in this study a new form of senescence, which is not dependent on activation of the DDR pathway but instead dependent on activation of the SSBR pathway. This form of senescence could be the most common one occurring in vivo because it involves epithelial cells and ensues from chronic oxidative stress.…”

“…1). 2 Thus, we have revealed an unsuspected role for SSBs in senescence and demonstrated that they are an initial cause of the upregulation of p16.…”

“…1). 2 SSBs are repaired by a pathway that initially involves a poly (ADP)ribose polymerase (PARP), predominantly PARP1, which senses the breaks. Once bound to DNA, PARP1 synthetizes poly(ADP)riboses (PARs) that accumulate at the break.…”

“…Indeed, depletion of PARP1 alone recapitulated XRCC1 foci accumulation, occurrence of senescence, and emergence of mutated and transformed cells. 2 Moreover, we knew from previous studies that senescence and neoplastic emergence in keratinocytes were dependent on oxidative stress. 5,10 Here, we further revealed that oxidative stress functions both as the source of SSBs and as the inducer of PARP1 downregulation at the messenger level.…”