Edited by John M. Denu Blunted melanocortin 1 receptor (MC1R) signaling promotes melanocyte genomic instability in part by attenuating cAMPmediated DNA repair responses, particularly nucleotide excision repair (NER), which recognizes and clears mutagenic photodamage. cAMP-enhanced NER is mediated by interactions between the ataxia telangiectasia-mutated and Rad3-related (ATR) and xeroderma pigmentosum complementation group A (XPA) proteins. We now report a critical role for sirtuin 1 (SIRT1) in regulating ATR-mediated phosphorylation of XPA. SIRT1 deacetylates XPA at residues Lys-63, Lys-67, and Lys-215 to promote interactions with ATR. Mutant XPA containing acetylation mimetics at residues Lys-63, Lys-67, and Lys-215 exhibit blunted UV-dependent ATR-XPA interactions even in the presence of cAMP signals. ATR-mediated phosphorylation of XPA on Ser-196 enhances cAMP-mediated optimization of NER and is promoted by SIRT1-mediated deacetylation of XPA on Lys-63, Lys-67, and Lys-215. Interference with ATR-mediated XPA phosphorylation at Ser-196 by persistent acetylation of XPA at Lys-63, Lys-67, and Lys-215 delays repair of UV-induced DNA damage and attenuates cAMP-enhanced NER. Our study identifies a regulatory ATR-SIRT1-XPA axis in cAMPmediated regulation melanocyte genomic stability, involving SIRT1-mediated deacetylation (Lys-63, Lys-67, and Lys-215) and ATR-dependent phosphorylation (Ser-196) post-translational modifications of the core NER factor XPA.

Homozygous loss of function of the melanocortin 1 receptor (MC1R) is associated with a pheomelanotic pigment phenotype and increased melanoma risk. MC1R heterozygosity is less well studied, although individuals inheriting one loss-of-function MC1R allele are also melanomaprone. Using the K14-Scf C57BL/6J animal model whose skin is characterized by life-long retention of interfollicular epidermal melanocytes like that of the human, we studied pigmentary, UV responses and DNA repair capacity in the skin of variant Mc1r background. Topical application of forskolin, a skin-permeable pharmacologic activator of cAMP induction to mimic native Mc1r signaling, increased epidermal eumelanin levels, increased the capacity of Mc1rheterozygous skin to resist UV-mediated inflammation, and enhanced the skin's ability to clear UV photolesions from DNA. Interestingly, topical cAMP induction also promoted melanin accumulation, UV resistance, and accelerated clearance in Mc1r fully-intact skin. Together, our findings suggest that heterozygous Mc1r loss is associated with an intermediately melanized and DNA repair-proficient epidermal phenotype and that topical cAMP induction enhances UV resistance in Mc1r-heterozygous or -wild type individuals by increasing eumelanin deposition and by improving nucleotide excision repair.

Differences in Rural-Urban Breast ReconstructionThis article is protected by copyright. All rights reserved.2 Background: Breast reconstruction (BR) is the reconstructive surgical technique that focuses on restoring normal form and function to the breast following oncologic resection. The goal of this study was to determine if BR disparities exist among rural female patients in Kentucky.Methods: A retrospective (2006 -2015), population-based cohort study was conducted on breast cancer patients (stages I-III) treated with mastectomy with or without BR. We used 2013 Beale codes to stratify patients according to geographic status. Chi-square tests were used to examine the association of BR along the rural-urban continuum. A multivariate logistic regression model controlling for patient, disease, and treatment factors was used to predict BR. The likelihood of BR was reported in odds ratios (OR) using a 95% confidence interval (CI).Results: Overall, 10,032 patients met study criteria. Of those, 2,159 (21.5%) underwent BR. The rate of BR among urban, near-metro, and rural patients was 31.1%, 20.4%, and 13.4%, respectively (P < .001). Multivariate analysis revealed that women from near metro (OR 0.54, CI: 0.47-0.61; P < .001) and rural areas (OR 0.36, CI: 0.31-0.41; P < .001) were less likely to undergo BR than women from urban areas. Conclusion:Although BR benefits are well documented, women from rural Kentucky undergo BR at lower rates and are less likely to receive BR than their urban counterparts. Efforts should seek to promote equitable access to BR for all patients, including those from rural areas.