Scientists gain new insight into UV-exposure genetics

The UV Radiation Resistance-Associated Gene has earned its clunky name: It’s been linked to a rare genetic disease called xeroderma pigmentosum that makes sufferers extremely vulnerable to sun exposure. So much, in fact, that their risk of skin cancer is thought to skyrocket by 1,000 times.

But it’s not been clear how the gene actually works or what happens when it goes haywire. Now, we’re getting closer to an answer. New research finds that the gene plays a big role in the skin’s response to UV rays, raising the prospect that it could be a biomarker identifying those at special risk for melanoma from sun exposure.

“We established for the first time that the gene is a key player in UV-induced DNA damage repair,” says Chengyu Liang, M.D., Ph.D., lead author of the recent study about this gene.¹ “We’ve deciphered how it works and why it is important for UV protection,” says Dr. Liang.

In the big picture, scientists still have much to learn about links between genetics and skin cancer, says Dr. Liang, an associate professor with the Department of Molecular Microbiology & Immunology at the University of Southern California’s Keck School of Medicine. “Different kinds of skin cancer differ in their genetics,” she says. “The exact genetic factors for skin cancer remain a mystery.”

In terms of melanoma specifically, she tells Dermatology Times, several gene mutations appear to be connected to the disease, but there’s no single one that directly causes it. “In addition, mutations or deficiency of genes involved in repair of UV-induced DNA damage are directly linked to dramatically increased melanoma risk,” she says.

The American Cancer Society estimates that 10,130 people will die of melanoma in the U.S. in 2016, accounting for a huge majority of skin cancer deaths. Sun exposure is thought to be responsible for a large percentage of melanoma cases; research suggests that regular sunscreen use can dramatically reduce the number of cases.  

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The UV Radiation Resistance Associated Gene, a protein coding gene, has been connected to the xeroderma pigmentosum disease, which affects an estimated 1 in 1 million people in the U.S. and Europe. It causes extreme sensitivity to UV rays that results in severe sunburns and freckling, even in kids under 2. Most patients develop multiple skin cancer lesions, sometimes before age 10.

Researchers have linked the gene to autophagy, membrane trafficking, chromosome stability, and other roles, Dr. Liang says. But none of these functions explain its role in UV protection.

Enter the new study. Dr. Liang and colleagues tinkered with the gene in melanoma cells and fly eyes. The researchers linked the alternate copies of the gene to more damage from UV exposure due to an impaired repair process within cells.

In addition, Dr. Liang says, “we compared melanoma patients with and without these variations, and those with the normal form have a better survival rate.”

What does all this mean? “Genetic deficiency of some factors involved in UV damage repair will significantly enhance the risk of skin cancer patients to UV radiation, leading to increased disease progression,” Dr. Liang says. “Appropriate protection from excessive UV for these genetically weak patients such as covering up more and lathering on more sunscreen will help prevent against UV induced damage and reduce skin cancer risk.”

Jeffrey Salomon, M.D., FACS, assistant clinical professor of surgery (plastic) at Yale University School of Medicine, tells Dermatology Times that the research “helps pull back the curtain a little” on the role of genetics in melanoma.

According to Dr. Salomon, the study shows that the UV Radiation Resistance Associated Gene is an “important factor” in the nucleotide excision repair pathway, which consists of at least 5 steps that repair damaged cells. “It is this pathway that protects the skin from UV-induced mutations.”

What now?

It’s not clear whether the dangerous variations in the gene are common, Dr. Liang. But eventually, the gene could become a biomarker, she says, and be used to identify patients who are more sensitive to UV exposure and will need early protection. “Further work in preclinical models and some human genetic studies will be necessary to confirm this,” says Dr. Liang.

Moving forward, she says, “We will further investigate the mechanism by which the UV-resistant gene functions in skin cancer prevention and treatment.”

References:

1. Yang Y, He S, Wang Q, et al. Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase. Mol Cell. 2016;62(4):507-19.