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Article Dans Une Revue Molecular Neurobiology Année : 2019

ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

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In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS)may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNAdamage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our resultsrevealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated byincreasedγH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2displayed key hallmarks of senescent cells, includingdramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression andpositive senescence-associatedβ-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic ad-ministration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8(SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescenceand contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentiallypostpone cochlear aging and prevent ARHL in humans.
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hal-02269498 , version 1 (31-05-2022)

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Nesrine Benkafadar, Florence François, Corentin A. Affortit, François Casas, Jean-Charles Ceccato, et al.. ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation. Molecular Neurobiology, 2019, 56 (8), pp.5950-5969. ⟨10.1007/s12035-019-1493-6⟩. ⟨hal-02269498⟩
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