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 melanoma-prone. Using the K14-Scf C57BL/6J animal model whose skin is characterized by lifelong 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 Mc1r-heterozygous 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 Mc1r-wild-type individuals by increasing eumelanin deposition and by improving nucleotide excision repair.
|Number of pages
|Pigment Cell and Melanoma Research
|Published - Jan 1 2020
Bibliographical noteFunding Information:
This work was supported by the following NIH grants: R01CA131075, T32CA160003, P30CA177558, and P30ES026529. We thank the Regina Drury Pediatric Research Endowed Chair Fund, the Markey Cancer Foundation, the Melanoma Research Alliance, and the DanceBlue Golden Matrix Fund for their support. We acknowledge the critical contribution of the Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center. We thank James Sheppard III and Michael Jax of the University of Kentucky Department of Surgery for assistance with photography and image analysis. We thank Dr. Hong Pu for technical assistance. This manuscript's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
- DNA repair
- UV radiation
- melanocortin 1 receptor (MC1R)
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)