Serious sun science

[Bill]

UV damage and DNA repair in malignant melanoma and nonmelanoma skin cancer.

Rass K, Reichrath J.

Clinic for Dermatology, Venerology and Allergology, The Saarland University Hospital, 66421 Homburg/Saar, Germany. knuth.rass@uks.eu

Exposition of the skin with solar ultraviolet radiation (UV) is the main cause of skin cancer development. The consistently increasing incidences of melanocytic and nonmelanocytic skin tumors are believed to be at least in part associated with recreational sun exposure. Epidemiological data indicate that excessive or cumulative sunlight exposition takes place years and decades before the resulting malignancies arise. The most important defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The important function of nucleotide excision DNA repair (NER) to protect against skin cancer becomes obvious by the rare genetic disease xeroderma pigmentosum, in which diverse NER genes are mutated. In animal models, it has been demonstrated that UVB is more effective to induce skin cancer than UVA. UV-induced DNA photoproducts are able to cause specific mutations (UV-signature) in susceptible genes for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In SCC development, UV-signature mutations in the p513 tumor suppressor gene are the most common event, as precancerous lesions reveal approximately 80% and SCCs > 90% UV-specific p53 mutations. Mutations in Hedgehog pathway related genes, especially PTCH1, are well known to represent the most significant pathogenic event in BCC. However, specific UV-induced mutations can be found only in approximately 50% of sporadic BCCs. Thus, cumulative UVB radiation can not be considered to be the single etiologic risk factor for BCC development. During the last decades, experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the south american oppossum and human skin xenografts, have further elucidated the important role of the DNA repair system in the multi-step process of UV-induced melanomagenesis. An increasing body of evidence now indicates that nucleotide excision repair is not the only DNA repair pathway that is involved in UV-induced tumorigenesis of melanoma and nonmelanoma skin cancer. An interesting new perspective in DNA damage and repair research lies in the participation of mammalian mismatch repair (MMR) in UV damage correction. As MMR enzyme hMSH2 displays a p53 target gene, is induced by UVB radiation and is involved in NER pathways, studies have now been initiated to elucidate the physiological and pathophysiological role of MMR in malignant melanoma and nonmelanoma skin cancer development.
PMID: 18348455 [PubMed - indexed for MEDLINE]

[Bill]

The most important defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms.

In other words, a tan and the body's ability to repair DNA damage are the most important defense mechanisms against any UV damage to the skin.

Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures.

People that can't tan and people that have defects in their DNA repair capabilities are the primary persons at risk for skin cancer

However, specific UV-induced mutations can be found only in approximately 50% of sporadic BCCs. Thus, cumulative UVB radiation can not be considered to be the single etiologic risk factor for BCC development.

Here is where it gets more tricky. UV radiation causes occasional damage at the cellular level. (So do a lot of other things, but let's just talk about UV for a moment.) Normally, your body sees this damage and simply kills off the defective cell. If your body doesn't recognize the cell as defective, it can continue to reproduce copies of itself and that is what becomes a cancer. UV damage to cells leaves a recognizable signature. Only about half of the basal cell carcinomas that are studied were caused by UV damage. So, what caused the others to mutate? Eliminating UV exposure would not eliminate skin cancer.

During the last decades, experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the south american oppossum and human skin xenografts, have further elucidated the important role of the DNA repair system in the multi-step process of UV-induced melanomagenesis. An increasing body of evidence now indicates that nucleotide excision repair is not the only DNA repair pathway that is involved in UV-induced tumorigenesis of melanoma and nonmelanoma skin cancer.

Nucleotide excision repair is the mechanism that recognizes DNA defects. Doctors and scientists look at the fact that UV light causes damage to the DNA in a cell and assume that, if the cell wasn't damaged by the UV, they could eliminate the cancer. However, your body has numerous causes of cellular damage.
Exogenous factors (influences from outside the body )can be divided into:

• mechanical (traumatic injury),
• physical (extremely low or high temperature, ionising irradiation including UV, microwaves),
• chemical (caustic agents, poisons, venoms, genotoxic and proteotoxic compounds),
• nutritive (deficiency of oxygen, vitamins and basic nutrients),
• biological (viruses, microorganisms, protozoan and metazoan parasites).

Your body's ability to repair cellular damage is a vital part of staying alive.

An interesting new perspective in DNA damage and repair research lies in the participation of mammalian mismatch repair (MMR) in UV damage correction. As MMR enzyme hMSH2 displays a p53 target gene, is induced by UVB radiation and is involved in NER pathways, studies have now been initiated to elucidate the physiological and pathophysiological role of MMR in malignant melanoma and nonmelanoma skin cancer development.

In spite of all the great strides we have made over the last few years, there are still things we don't know about how our body works on a cellular level.