DNA, sunlight and skin cancer

Mutations in the p53 tumor suppressor genes in the most common types of skin cancer occur almost exclusively at dipyrimidine sites and are highly characteristic of UVB light. The UVB in sunlight produces cis-syn dimers and (6-4) products at dipyrimidine sites, the latter of which are isomerized by UVA/B light to their Dewar valence isomers. Which of these photoproduct classes is primarily responsible for the mutagenic and carcinogenic effects of sunlight is unknown and to approach this problem we have been developing methods for the construction and study of DNA containing unique photoproducts. Our studies have led us to a new proposal for the origin of C+T mutations, the principal mutations induced by UVB light in many living systems and the major mutation found in the human p53 gene. Introduction. Skin cancer is the most prevalent form of cancer in the United States and will affect approximately 1 in 4 Americans in their lifetime. There are three major types of skin cancer, basal cell carcinoma (500,000 casedyr, 500 deathdyr), squamous cell carcinoma (1 20,000 cases/year, 1,500 deaths /yr) and melanoma (32,000 new casedyear, 6,500/yr). These cancers arise in the corresponding cells of the epidermis which is on average about 100 microns thick, corresponding to the penetration depth of UVB light. The basal cells differentiate into squamous cells which then migrate to the surface over a period of a month and are sloughed off The melanocytes produce melanosomes which produce the highly UV absorbing melanin. Of the three types of skin cancer, basal and squamous cell carcinomas correlate the best with exposure to sunlight. The correlation between UV damage to DNA and skin cancer comes from a number of important observations. The first evidence came from very early studies (late 30's) that demonstrated that the effectiveness of UV light in causing cell death or inducing mutations paralleled the absorption spectrum of nucleic acids and not proteins (for a review see ref. 1). It wasn't until the early -M N-M'N'replication -M'Nuv DNA synthesis -x,Yrepair or _____) -XY-b -X=Y-)('bypass -"'repair 60's that the major photoproduct of DNA was isolated and identified as the cis-syn cyclobutane dimer of dipyrimidine sites (for a review of early work see ref. 2). The key piece of evidence linking photoproducts in DNA with skin cancer induction came from a seminal study on the genetic disease xeroderma pigmentosum (XP) which is associated with a 2000-fold higher incidence of skin cancer. Cleaver was able to demonstrate that cells of those aMicted with XP had defects in their ability to repair cis-syn dimers thus correlating a failure to repair DNA photodamage with skin cancer induction (3). Most recently it has been discovered that the p53 tumor suppressor gene of the most common types of skin cancer, basal cell and squamous cell carcinomas, contain a very high percentage of C+T mutations at dipyrimidine sites, including the CC+TT mutation highly characteristic of UVB induction (4, 5). Dipyrimidine sites are also the principal target of UVB-induced DNA damage suggesting that the mutations result from DNA synthesis errors that occur during DNA synthesis past the photoproduct. The photoproducts and mechanisms by which these mutations arise are not well understood, primarily because of a lack of methods for preparing DNA substrates containing site-specific adducts for the required biological studies.