Xeroderma Pigmentosum Group C Deficiency Alters Cigarette Smoke DNA Damage Cell Fate and Accelerates Emphysema Development

Abstract

Cigarette smoke (CS) exposure is a major risk factor for the development of emphysema, a common disease characterized by loss of cells comprising the lung parenchyma. The mechanisms of cell injury leading to emphysema are not completely understood but are thought to involve persistent cytotoxic or mutagenic DNA damage induced by CS. Using complementary cell culture and mouse models of CS exposure, we investigated the role of the DNA repair protein, xeroderma pigmentosum group C (XPC), on CS-induced DNA damage repair and emphysema. Expression of XPC was decreased in mouse lungs after chronic CS exposure and XPC knockdown in cultured human lung epithelial cells decreased their survival after CS exposure due to activation of the intrinsic apoptosis pathway. Similarly, cell autophagy and apoptosis were increased in XPC-deficient mouse lungs and were further increased by CS exposure. XPC deficiency was associated with structural and functional changes characteristic of emphysema, which were worsened by age, similar to levels observed with chronic CS exposure. Taken together, these findings suggest that repair of DNA damage by XPC plays an important and previously unrecognized role in the maintenance of alveolar structures. These findings support that loss of XPC, possibly due to chronic CS exposure, promotes emphysema development and further supports a link between DNA damage, impaired DNA repair, and development of emphysema.

DNA repair as an emerging target for COPD-lung cancer overlap

“…Others have reported that exposure of mice to side stream smoke (up to 16 weeks) decreases expression of the DNA repair proteins, XPC and OGG1, and decreases NER and BER activity [111]. We have recently demonstrated an important role of XPC in the prevention of emphysema-like lung disease with aging in mice exposed to chronic cigarette smoke [87]. Xpc -/mice develop increased lung compliance and alveolar rarefication with age, which is further increased by chronic cigarette smoke exposure [87].…”

“…This is further supported by epidemiological studies, which have proposed a link between common XPC polymorphisms and lung cancer development [108][109][110]. Exposure of C57Bl/6 mice to 6 months of cigarette smoke leads to decreased expression of XPC mRNA compared to littermates exposed to ambient air, but no change in the expression of other measured DNA repair proteins involved in the NER and BER pathways [87]. Others have reported that exposure of mice to side stream smoke (up to 16 weeks) decreases expression of the DNA repair proteins, XPC and OGG1, and decreases NER and BER activity [111].…”

“…However, these results were almost certainly confounded by increased cigarette use in the COPD group compared to the controls (86). Polymorphisms of XPC, XPA, and XRCC5 (Ku80) genes have been associated with an increased risk of COPD and have also been implicated in cancer development [87][88][89][90][91]. Specific polymorphisms of DNA repair proteins believed to increase COPD risk may not correlate with lung cancer risk, as seen in the analysis performed by deAndrade et al, and may vary by tobacco use and specific alleles analyzed [85,92].…”

“…We have recently demonstrated an important role of XPC in the prevention of emphysema-like lung disease with aging in mice exposed to chronic cigarette smoke [87]. Xpc -/mice develop increased lung compliance and alveolar rarefication with age, which is further increased by chronic cigarette smoke exposure [87]. XPC has also been identified as important factor in cancer development, with its best-characterized role in protecting against UV-induced skin cancers [112].…”

Decreased miR-24-3p potentiates DNA damage responses and increases susceptibility to COPD

“…DNA damage is a well-described consequence of CS exposure and growing evidence from genetic association studies and animal models of disease have suggested an important role for cellular responses to DNA damage in the pathobiology of COPD (4)(5)(6)(7)(8). DNA damage occurs in all cells from endogenous (e.g.…”