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UV-Induced DNA Damage and Repair UV-Induced DNA Damage Bacteriologists discovered in the 19th Century that direct sunlight exposure was lethal to bacteria and other microorganisms. Subsequent studies over many years eventually showed the lethal action of sunlight to be primarily attributable to the UV portion of the spectrum near 260 nm. This corresponds to the Amax for the DNA bases, whereas the Amax for proteins is near 280 nm. UV irradiation is a widely used a method for decontamination by "germicidal lamps". UV-induced mutagenicity (as opposed to UV-induced lethality)for bacteria was demonstrated in 1914 by V. Henri, 13 years before Muller’s celebrated demonstration of X-ray-induced mutagenesis in Drosophila. Henri's discovery was not followed up because many people at that time did not believe that bacteria even had genes or genetic systems! It was not until the ascendance of bacteriophage genetics in the 1940’s that Demerec sdemonstrated a 103 X enrichment of E. coli T1-resistant mutants among 10-4 survivors of a UV irradiated culture. UV-induced DNA lesions are covalently crosslinked DNA bases, primarily cyclopyrimidine dimers (CPD’s) involving adjacent tymines in the same DNA strand, and 6,4 adducts of adjacent pyrimidines in the same strand. Crosslinks are lethal to cells because they block DNA replication. UV-induced crosslinking also occurs during visualization of DNA in agarose gels with a UV transilluminator, so the effect occurs in vitro as well as in vivo. Several repair mechanisms are known to mitigate the lethality of DNA photolesions in E.coli. Repair of UV-Induced DNA Damage by Photolyases “Photoreactivation” is the term suggested by Delbrück for the phenomenon reported by Kelner (1949) in Streptomyces griseus. Following a UV exposure sufficient to reduce survivors to 10-5, subsequent exposure to visible light raises survivors to 10-1. Photoreactivation requires the visible light exposure AFTER the UV exposure. The productivity of visible exposure decreases to background over 2 hours in E. coli. Many organisms exhibit photoreactivation. Photoreactivation is due the activity of a class of enzymes known as DNA photolyases. CPD Photolyases Single subunit protein. Bind to CPD lesions in dark. Catalyze reversal following exposure to 370 nm light. 2 Prosthetic groups FADH•EITHER 5,10methylenetetrahydrofolate (MTHF) (see Horton Section 7.9) OR 8-hydroxy-5deazaflavin) as the "antenna chromophore". Excision Repair Many versions of DNA excision repair mechanisms are known, with specificity for various types of lesion. Excision repair of TT dimers in E. coli was the first such mechanism characterized. Activity of uvrABC exinuclease is specific for removal of UV photolesions. Gap repair is common to various excision repair scenarios. UV MUTAGENESIS UV-Induced mutagenesis in E. coli is based on "error-prone" translesion DNA synthesis.