Melanoma-associated melanocortin 1 receptor variants confer redox signaling-dependent protection against oxidative DNA damage
María Castejón-Griñán,
Sonia Cerdido,
José Sánchez-Beltrán,
Ana Lambertos,
Marta Abrisqueta,
Cecilia Herraiz,
Celia Jiménez-Cervantes,
José Carlos García-Borrón
Affiliations
María Castejón-Griñán
Corresponding author.; Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
Sonia Cerdido
Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
José Sánchez-Beltrán
Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
Ana Lambertos
Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
Marta Abrisqueta
Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
Cecilia Herraiz
Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
Celia Jiménez-Cervantes
Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
José Carlos García-Borrón
Corresponding author.; Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), El Palmar, Murcia, Spain
Cutaneous melanoma, a lethal skin cancer, arises from malignant transformation of melanocytes. Solar ultraviolet radiation (UVR) is a major environmental risk factor for melanoma since its interaction with the skin generates DNA damage, either directly or indirectly via oxidative stress. Pheomelanin pigments exacerbate oxidative stress in melanocytes by UVR-dependent and independent mechanisms. Thus, oxidative stress is considered to contribute to melanomagenesis, particularly in people with pheomelanic pigmentation. The melanocortin 1 receptor gene (MC1R) is a major melanoma susceptibility gene. Frequent MC1R variants (varMC1R) associated with fair skin and red or yellow hair color display hypomorphic signaling to the cAMP pathway and are associated with higher melanoma risk. This association is thought to be due to production of photosensitizing pheomelanins as well as deficient induction of DNA damage repair downstream of varMC1R. However, the data on modulation of oxidative DNA damage repair by MC1R remain scarce. We recently demonstrated that varMC1R accelerates clearance of reactive oxygen species (ROS)-induced DNA strand breaks in an AKT-dependent manner. Here we show that varMC1R also protects against ROS-dependent formation of 8-oxodG, the most frequent oxidative DNA lesion. Since the base excision repair (BER) pathway mediates clearance of these DNA lesions, we analyzed induction of BER enzymes in human melanoma cells of varMC1R genotype. Agonist-mediated activation of both wildtype (wtMC1R) and varMC1R significantly induced OGG and APE-1/Ref1, the rate-limiting BER enzymes responsible for repair of 8-oxodG. Moreover, we found that NADPH oxidase (NOX)-dependent generation of ROS was responsible for AKT activation and oxidative DNA damage repair downstream of varMC1R. These observations provide a better understanding of the functional properties of melanoma-associated MC1R alleles and may be useful for the rational development of strategies to correct defective varMC1R responses for efficient photoprotection and melanoma prevention in fair-skinned individuals.
