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Updated: Mar 8, 2026
Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model
Published on: September 7, 2013
Divergence of cAMP signalling pathways mediating augmented nucleotide excision repair and pigment induction in
Erin M Wolf Horrell1,2, Stuart G Jarrett3,2, Katharine M Carter2
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.
Abstract:
Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are common in UV-sensitive fair-skinned individuals and are associated with blunted cAMP second messenger signalling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signalling positions melanocytes to resist UV injury by upregulating synthesis of UV-blocking eumelanin pigment and by enhancing the repair of UV-induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP-activated protein kinase (protein kinase A)-mediated phosphorylation of the ataxia telangiectasia-mutated and Rad3-related (ATR) protein on the S435 residue. We investigated the interdependence of cAMP-mediated melanin upregulation and cAMP-enhanced DNA repair in primary human melanocytes and a melanoma cell line. We observed that the ATR-dependent molecular pathway linking cAMP signalling to the NER pathway is independent of MITF activation. Similarly, cAMP-mediated upregulation of pigment synthesis is independent of ATR, suggesting that the key molecular events driving MC1R-mediated enhancement of genome maintenance (eg PKA-mediated phosphorylation of ATR) and MC1R-induced pigment induction (eg MITF activation) are distinct.
Insights
Loss-of-function melanocortin 1 receptor (MC1R) variants impair skin
Area of Science:
- Molecular Biology
- Dermatology
- Genetics
Background:
- Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are linked to UV sensitivity and increased melanoma risk.
- MC1R signaling influences melanocyte responses to UV damage, including DNA repair and pigment production.
- Cyclic AMP (cAMP) signaling enhances DNA repair via protein kinase A (PKA) phosphorylation of ATR.
Purpose of the Study:
- To investigate the interdependence of cAMP-mediated melanin synthesis and DNA repair enhancement in melanocytes.
- To elucidate the molecular pathways linking MC1R signaling to UV protection mechanisms.
Main Methods:
- Experiments conducted on primary human melanocytes and a melanoma cell line.
- Analysis of cAMP signaling pathways, melanin production, and DNA repair mechanisms (nucleotide excision repair - NER).
- Investigated the role of ATR and MITF in these processes.
Main Results:
- The ATR-dependent pathway linking cAMP to DNA repair is independent of MITF activation.
- cAMP-mediated melanin synthesis upregulation is independent of ATR.
- Distinct molecular events mediate MC1R's effects on genome maintenance and pigment induction.
Conclusions:
- MC1R signaling activates separate pathways for enhancing DNA repair and increasing melanin production.
- These distinct pathways highlight the complex molecular mechanisms underlying UV protection in melanocytes.
- Understanding these pathways could inform strategies for melanoma prevention and treatment.
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