Melanin content and MC1R function independently affect UVR‐induced DNA damage in cultured human melanocytes

Abstract

Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)-induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR-induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR-induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR-induced DNA damage in melanocytes.

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

“…41 The loss of function variants within the MC1R gene are associated with increased UV induced DNA damage and apoptosis; reduced repair and photoprotection due to formation of free radical generating phaeomelanin that can lead to DNA strand breaks. 42,43 According to the multistage models of cancer, multiplicative interactions have been interpreted as 2 exposures (the MC1R variants and common allele of the XRCC3 polymorphism in the present study) affecting different stages. 44,45 In the context of the observed results we hypothesize the probable perturbation of apoptosis by the XRCC3 variant allele, which in turn could be triggered by UV-phaeomelanin generated DNA strand breaks.…”

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

“…Molecular analysis has revealed that MC1R signaling modulates the expression and function of the microphthalmia-associated transcription factor, a key regulator of pigmentation genes, suggesting that this pathway underlies MC1R coordination of melanogenesis (16). Accumulating evidence suggests the photo-protective effect of MC1R signaling goes beyond quantitative and qualitative changes in melanin synthesis and extends to protection against UVinduced genomic damage via the induction of nucleotide excision repair mechanisms (17)(18)(19). Although variant MC1R is anticipated to have a significant effect on melanocyte gene expression, few downstream transcriptional targets of MC1R signaling have been identified to date (20 -22) and the differential transcriptional response between wild-type and RHC signaling remains poorly understood.…”

Ultraviolet Light as a Modulator of Melanoma Development

“…However the notion of UVR-induced melanocyte proliferation being melanomagenic is at odds with findings that stimulation of melanocytes with factor such as a-MSH (e.g. Bohm et al, 2005;Hauser et al, 2006;Abdel-Malek et al, 2009), Endothelin 1, (Kadekaro et al, 2005) and KITL (Serre et al, 2011) improve DNA repair efficiency after UVR and are thus proposed to be protective for melanoma. Clearly we are only at the beginning of understanding how melanocyte UVR responses influence melanoma development.…”

“…In addition, pheomelanin is more likely than eumelanin to generate potentially damaging reactive oxygen species following UVR exposure (Hill, 1992;Takeuchi et al, 2004;Baldea et al, 2009). A popular explanation for the protective role of MC1R comes from cell culture experiments showing that melanocytes carrying melanoma-associated MC1R variants have less effective repair of both UVR-induced pyrimidine dimers and oxidative damage than wild-type cells and are more sensitive to UVR-induced cell death (Kadekaro et al, 2005;Bohm et al, 2005;Hauser et al, 2006;Song et al, 2009). Functional MC1R appears to be necessary to prevent UV-induced genomic instability within melanocytes.…”