It seems fitting that, as I write this blog entry, I am soaking up a bit of sun on a dock on a small northern Wisconsin lake. I’ve deployed many of my normal defenses against the sun’s harmful rays, including a big floppy hat and plenty of sunscreen. Recently, I learned that, as a redhead, I have another defense—a cellular defense—against the dangerous results of ultraviolet light exposure: the very same genetic mutation in the MC1R gene that probably makes my hair red in the first place.

Doctors have known for years that people with pale skin are more susceptible to melanoma, but just recently, we have learned that these same people have a higher overall survival rate than people with darker complexions and hair color (1). In a recent Pigment Cell & Melanoma Research article, which combined data from ten smaller studies that followed the prognosis of more than 3,000 melanoma patients, John Davies et al. reported that, while people with pale skin and red hair have a higher risk of developing melanoma compared to individuals with dark hair, a ginger’s overall survival rate is significantly higher.

So, what makes a mutation in the melanocortin 1 receptor (MC1R) one of a redhead’s best weapons in the fight against this deadly disease? MC1R is a G-protein-coupled receptor perhaps best known for its role in regulating pigment biosynthesis in melanocytes. Signaling through MC1R results in synthesis of black and brown pigments (eumelanin), which mask the lighter pigment, pheomelanin, resulting in dark hair. Faulty MC1R signaling interferes with eumelanin biosynthesis and results in red or blond hair. However, MC1R affects more than just pigmentation. MC1R activates the microphthalmia-associated transcription factor (MITF) pathway, which regulates expression of genes encoding DNA repair enzymes and proteins involved in cell cycle regulation, apoptosis and metastasis—all genes that are associated with carcinogenesis.

When cells are exposed to agents that damage DNA, such as ultraviolet light, protective cellular mechanisms detect and repair the damage or, if the damage is too great, initiate apoptosis. Thus, DNA repair activity is critical to allow cancer cells to escape apoptosis and divide. For example, studies have shown that overexpression of DNA repair pathway components in cancer cells is associated with metastasis and poor patient prognosis (2,3). In cultured melanoma cells, downregulation of the specific DNA repair gene product APEX1 results in apoptosis (4), and Kadekaro et al. (5) have shown that human melanocytes with two copies of the MC1R R allele, which is strongly associated with red hair, had reduced levels of alpha-melanocortin-mediated DNA repair. Based on this and other information, Davies et al. hypothesize that functional MC1R signaling increases levels of double-stranded DNA break repair, decreases apoptosis of cancer cells and/or increases cellular proliferation. Due to faulty MC1R activity in redheads, melanoma cells have a lower chance of escaping apoptosis and surviving to grow and divide.

So, does this mean that I don’t have to take as many Draconian measures to avoid the sun? Of course not. As a fair-skinned redhead, I am still more susceptible to skin cancer. However, it’s nice to know that I’ve got a secret weapon in the fight against melanoma.

References

1. Davies, J.R. et al. (2012). Inherited variants in the MC1R gene and survival from cutaneous melanoma: A BiogenoMEL study. Pigment Cell Melanoma Res. 25, 384–94. DOI: 10.1111/j.1755-148X.2012.00982.x
2. Jewell, R. et al. (2010). Patterns of expression of DNA repair genes and relapse from melanoma. Clin. Cancer Res. 16, 5211–21.
3. Winnepenninckx, V. et al. (2006). Gene expression profiling of primary cutaneous melanoma and clinical outcome. J. Natl. Cancer Inst. 98, 472–82.
4. Yang, S. et al. (2005). lterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor. Mol. Cancer Ther. 4, 1923–35.
5. Kadekaro, A.L. et al. (2010). Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J. 24, 3850–60.