Molecular clock dysfunction in lung cellular senescence by environmental tobacco smoke

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SUMMARY Environmental tobacco smoke (ETS) or “secondhand smoke” exposure leads to stress-induced adverse outcomes including cellular senescence and toxicological effects on the lungs associated with systemic injury and inflammation in airway disorders. We have recently reported that ETS disrupts circadian clock function, induces oxidative stress and stimulates abnormal inflammatory responses. REV-ERBα is a critical component of the molecular clock, which regulates the expression of core clock genes, pro-inflammatory and pro-senescent mediators. Our preliminary data suggest that ETS-mediated cellular senescence is dependent on irregular activity of the clock gene nuclear receptor REV-ERB in the lungs. Our preliminary data further show an impaired DNA repair and inflammatory response in molecular clock deficient REV-ERBα KO mice, suggesting the involvement of the clock protein REV-ERB in regulating DNA damage/repair. Further, REV-ERBα agonists reduce ETS-induced levels of pro-inflammatory and pro-senescent mediators. However, the role of molecular clock dysfunction in chronic ETS-mediated DNA damage/repair, cellular senescence, and toxicological effects remains unknown. Sirtuin 1 (SIRT1), a protein/histone deacetylase, is reduced by ETS, resulting in cellular senescence, oxidative stress and abnormal inflammatory responses. Our preliminary data show that SIRT1 regulates REV-ERBα abundance. However, it is not known whether SIRT1 regulates lung cellular senescence and inflammatory responses through a REV-ERBα-dependent mechanism. We hypothesize that ETS disrupts molecular clock function, specifically REV-ERBα abundance, resulting in DNA damage-initiated cellular senescence through a SIRT1-dependent mechanism in pulmonary toxicity. We propose to test this hypothesis by determining the impact of ETS-induced REV-ERBdisruption on cellular senescence, DNA damage/repair, and toxicological responses in a mouse model based on the following three Aims: Aim 1: Determine the molecular mechanism through which ETS-mediated disruption of REV- ERBmolecular clock function leads to cellular senescence and senescence-associated inflammatory phenotype (SASP); Aim 2: Determine the involvement of REV-ERB in DNA repair by non-homologous end joining (NHEJ) during cellular senescence following ETS exposure; and Aim 3: Determine the role of SIRT1 in regulating REV-ERB and DNA damage-induced lung cellular senescence following ETS. The outcome of this proposal will unravel the role of the molecular clock in regulating DNA damage-induced lung cellular senescence via a SIRT1-dependent mechanism during the xenobiotic response to ETS exposure. In turn, our findings will have great translational potential for the development of pharmacological therapies based on targeting molecular clock function to ameliorate lung cellular senescence and DNA damage following chronic exposure to ETS.