Replication stress-induced endogenous DNA damage drives cellular senescence induced by a sub-lethal oxidative stress

Abstract

Although oxidative stress has been shown to induce senescence and replication stress independently, no study has implicated unresolved replication stress as the driver for cellular senescence in response to oxidative stress. Using cells exposed to increasing concentrations of hydrogen peroxide, we show that sub-lethal amount of exogenous hydrogen peroxide induces two waves of DNA damage. The first wave is rapid and transient while the second wave coincides with the cells transition from the S to the G2/M phases of cell cycle. Subsequently, cells enter growth arrest accompanied by the acquisition of senescence-associated characteristics. Furthermore, a p53-dependent decrease in Rad51, which is associated with the formation of DNA segments with chromatin alterations reinforcing senescence, and Lamin B1 that is involved in chromatin remodeling, is observed during the establishment of the senescent phenotype. On the other hand, increase in senescence associated-β-Gal activity, a classical marker of senescence and HMGA2, a marker of the senescence-associated heterochromatin foci, is shown to be independent of p53. Together, our findings implicate replication stress-induced endogenous DNA damage as the driver for the establishment of cellular senescence upon sub-lethal oxidative stress, and implicate the role of p53 in some but not all hallmarks of the senescent phenotype.

Organismal Aging and Oxidants beyond Macromolecules Damage

“…Using cells exposed to increasing concentrations of H 2 O 2 , we demonstrated that replication stress-induced endogenous DNA damage was responsible for the establishment of a deep cellular senescent phenotype in response to a sublethal oxidative stress. [89] Taken together, these studies clearly identify oxidants as key effectors of DNA damage leading to the activation of the DDR and cell cycle arrest the induction of cellular senescence. However, these data do not address a possible role for oxidants in the signaling pathways involved in the establishment of the senescent phenotype.…”

“…Although, oxidative stress and replication stress had been shown to induce senescence independently, our recently published work was the first report implicating unresolved replication stress as the driver of oxidative‐stress‐induced cellular senescence. Using cells exposed to increasing concentrations of H 2 O 2 , we demonstrated that replication stress‐induced endogenous DNA damage was responsible for the establishment of a deep cellular senescent phenotype in response to a sublethal oxidative stress …”

The emerging role of cellular senescence in renal diseases

“…17 Oxidative stress can induce DNA damage, which is an important mechanism related to stress-induced cellular senescence. 17 Oxidative stress can induce DNA damage, which is an important mechanism related to stress-induced cellular senescence.…”

Peer Review #1 of "Huperzine A attenuates nonalcoholic fatty liver disease by regulating hepatocyte senescence and apoptosis: an in vitro study (v0.1)"

“…Older age can increase the likelihood of NASH and fibrosis. Older age also increases the risk of death of those with NAFLD (Zhang et al, 2017;Venkatachalam et al, 2017). To study the role of oxidative stress in hepatocyte senescence, we selected an antioxidative agent, huperzine A, to treat an in vitro NAFLD model and tested the status of hepatocyte senescence.…”

“…These results revealed that the fatty liver cells had a senescence phenomenon. However, how the hepatocytes become senescent in NAFLD is not very clear.Studies report that oxidative stress plays an important role in cellular senescence and aging (Zhang et al, 2017; Gambino et al, 2013;Venkatachalam et al, 2017). Aging is delayed after inhibiting oxidative stress in mammals (Gambino et al, 2013).…”