No abstract

Background Autoimmune (AI) diseases appear to be a product of genetic predisposition and environmental triggers. Disruption of the skin barrier causes exacerbation of psoriasis/eczema. Oxidative stress is a mechanistic pathway for pathogenesis of the disease and is also a primary mechanism for the detrimental effects of air pollution. Methods We evaluated the association between autoimmune skin diseases (psoriasis or eczema) and air pollutant mixtures in 9060 subjects from the Personalized Environment and Genes Study (PEGS) cohort. Pollutant exposure data on six criteria air pollutants are publicly available from the Center for Air, Climate, and Energy Solutions and the Atmospheric Composition Analysis Group. For increased spatial resolution, we included spatially cumulative exposure to volatile organic compounds from sites in the United States Environmental Protection Agency Toxic Release Inventory and the density of major roads within a 5 km radius of a participant’s address from the United States Geological Survey. We applied logistic regression with quantile g-computation, adjusting for age, sex, diagnosis with an autoimmune disease in family or self, and smoking history to evaluate the relationship between self-reported diagnosis of an AI skin condition and air pollution mixtures. Results Only one air pollution variable, sulfate, was significant individually (OR = 1.06, p = 3.99E−2); however, the conditional odds ratio for the combined mixture components of PM2.5 (black carbon, sulfate, sea salt, and soil), CO, SO2, benzene, toluene, and ethylbenzene is 1.10 (p-value = 5.4E−3). Significance While the etiology of autoimmune skin disorders is not clear, this study provides evidence that air pollutants are associated with an increased prevalence of these disorders. The results provide further evidence of potential health impacts of air pollution exposures on life-altering diseases. Significance and impact statement The impact of air pollution on non-pulmonary and cardiovascular diseases is understudied and under-reported. We find that air pollution significantly increased the odds of psoriasis or eczema in our cohort and the magnitude is comparable to the risk associated with smoking exposure. Autoimmune diseases like psoriasis and eczema are likely impacted by air pollution, particularly complex mixtures and our study underscores the importance of quantifying air pollution-associated risks in autoimmune disease.

DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage and are repaired through non-homologous end-joining (NHEJ) or homologous recombination (HR). Repair initiation, regulation and communication with signaling pathways require several histone-modifying and chromatin-remodeling complexes. In budding yeast, this involves three primary complexes: INO80-C, which is primarily associated with HR, SWR1-C, which promotes NHEJ, and RSC-C, which is involved in both pathways as well as the general DNA damage response. Here we identify ARP6 as a factor involved in DSB repair through an RSC-C-related pathway. The loss of ARP6 significantly reduces the NHEJ repair efficiency of linearized plasmids with cohesive ends, impairs the repair of chromosomal breaks, and sensitizes cells to DNA-damaging agents. Genetic interaction analysis indicates that ARP6, MRE11 and RSC-C function within the same pathway, and the overexpression of ARP6 rescues rsc2∆ and mre11∆ sensitivity to DNA-damaging agents. Double mutants of ARP6, and members of the INO80 and SWR1 complexes, cause a significant reduction in repair efficiency, suggesting that ARP6 functions independently of SWR1-C and INO80-C. These findings support a novel role for ARP6 in DSB repair that is independent of the SWR1 chromatin remodeling complex, through an apparent RSC-C and MRE11-associated DNA repair pathway.

While most DNA lesions are repaired faithfully and without genotoxic effect, doublestranded breaks (DSBs) are exceptional. The deleterious potential of a misrepaired DSB represents a severe threat to cellular integrity. Repair machinery defects are frequently observed in tumorigenic and oncogenic cells. General DNA damage repair mechanisms involve homologous recombination (HR), or non-homologous end joining (NHEJ).Ongoing identification of new players in DSB repair leads us to believe there are more undiscovered genes in this pathway. The highly complex and conserved nature of DSB repair across eukaryotic and mammalian cells presents an opportunity for identification of novel genes through a computationally-directed approach. Employing a 'guilt-byassociation' model, we analyzed experimental and predicted interaction networks in S. cerevisiae to identify previously uncharacterized genes involved in repair. Three novel genes were discovered to influence repair-GAL7, YHI9, and YMR130W. The results of this study implicate all three in the DNA damage response network.iii