The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory's findings on the molecular mechanisms by which MC1R signaling impacts NER.
|Journal||Frontiers in Genetics|
|State||Published - May 31 2016|
Bibliographical noteFunding Information:
We acknowledge Dr. Stuart Jarrett for insights and key experimental discoveries seminal to our understanding of the molecular links between the melanocortin signaling axis and melanocyte UV resistance and DNA repair. We are grateful for support from the National Cancer Institute (R01 CA131075), the Melanoma Research Alliance (MRA) and the Regina Drury Endowment for Pediatric Research as well as T32CA165990 which supported EMW.
© 2016 Wolf Horrell, Boulanger and D'Orazio.
- DNA repair
ASJC Scopus subject areas
- Molecular Medicine