Molecular Life Sciences (2014)
Sunlight damage to DNA; UV damage to DNA
Sunlight is healthy and necessary in vitamin D activation, but it is also a major cause of skin cancer. UV light causes the formation of several DNA adducts, of which the most serious ones are cyclobutane dimers and pyrimidine-pyrimidone (6–4) photoproducts. Skin cancer can be understood in the context of these adducts, and a deficiency in DNA polymerase y, the translesion DNA polymerase that copies past the major adduct, gives rise to a form of the disease xeroderma pigmentosum.
Ultraviolet (UV) light is a major issue in human cancer because of skin cancer, which is a very significant problem. Aside from some chemicals that cause skin cancer (e.g., arsenic, which affects the skin in areas not exposed to light), skin cancer can be understood primarily in the context of DNA damage. Further, individuals deficient in certain DNA repair genes – or DNA polymerases required for efficient bypass of DNA damage, e.g., DNA polymerase y – show extreme sensitivity to damage and high risks of cancer (e.g., xeroderma pigmentosum).
Basis and relevance
Different wavelengths (energies) of light produce different types of damage. UV-A light exposure (320–400 nm) of the skin produces cyclobutane pyrimidine dimers (CPDs) (Fig. 1). UV-B radiation (290–320 nm) results in the formation of pyrimidine-pyrimidone (6–4) photoproducts. UV-C light (<290 nm) is not a general issue in that this is blocked by glass and ozone; sunlight is mainly UV-A and UV-B (Friedberg et al. 2006).
DNA photodamage can be reversed enzymatically by photolyases, enzyme systems present in most life forms. Reversal by these enzymes is also responsive to light (due to the presence of a fiavin and either a pterin or deazafiavin prosthetic group) and can reverse CPDs (to the original pyrimidines) (Friedberg et al. 2006). However, the enzymatic repair of UV damage involves a dominant role of the nucleotide excision repair (NER) pathway. Several of the types of xeroderma pigmentosum have had identified NER deficiencies.
Fig. 1. Two CPDs and a 6–4 dimer generated by UV treatment of DNA
The structural changes imposed in DNA by the CPDs are not severe. However, the 6–4 lesions strongly perturb the DNA duplex. A crystal structure of Sulfolobus solfataricus DNA polymerase Dpo4 has been obtained with an oligonucleotide containing a cis-syn CPD. Both of the thymines of the CPD fit into the active site of this Y-family DNA polymerase at the same time (Ling et al. 2003). Insertion of dATP opposite the 30 of the two thymines occurs with normal Watson-Crick base pairing; the second adenine (to be inserted) adopts a syn orientation to form a Hoogsteen pair. Efforts with replicative bacteriophage T7 DNA polymerase resulted in flipping of the CPD lesion out of the active site and leading to a loss of the closed conformation of the T7 polymerase (Li et al. 2004). More recently, Yang and her associates have published crystal structures of human DNA polymerase η containing a CPD (Biertumpfel et al. 2010). The enlarged active site of this Y-family DNA polymerase accommodates a thymine dimer, and there are a number of hydrogen bonds between the adduct and the protein.
Both yeast and human pol y can insert dGTP opposite the thymine-type ring of a 6–4 photoproduct, with low activity. B-Family member DNA polymerase z can insert dATP opposite the 50-thymidine-type ring with little reduction in catalytic efficiency. Pol i inserts dATP opposite the 30 ring of a 6–4 photoproduct. Thus, it is possible that these two DNA polymerases might work synergistically to bypass 6–4 blockage.
Biertumpfel C, Zhao Y, Kondo Y et al (2010) Structure and mechanism of human DNA polymerase eta. Nature 465:1044–1048
Friedberg EC, Walker GC, Siede W et al (2006) DNA repair and mutagenesis. ASM Press, Washington, DC
Li Y, Dutta S, Doublie S et al (2004) Nucleotide insertion opposite a cis-syn thymine dimer by a replicative DNA polymerase from bacteriophage T7. Nat Struct Mol Biol 11:784–790
Ling H, Boudsocq F, Plosky BS et al (2003) Replication of a cis-syn thymine dimer at atomic resolution. Nature 424:1083–1087