Alternative mechanisms for processing UV-induced DNA damage
| Although NER
processes are highly conserved, at least two other distinct mechanisms
exist for the removal of UV-induced DNA damage. As the enzymes involved
in these mechanisms exhibit significant specificity in lesion recognition,
they have been used extensively in order to experimentally distinguish
between the two major UV-photoproducts, CPDs and 6-4PPs.
There is commercial interest in using these types of enzymes in skin care products in order to reduce skin cancer risk (see for example AGI Dermatics). |
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Direct reversion of UV-induced photoproducts
| The E.coli enzyme photolyase
(or photoreactivating enzyme) specifically binds CPDs [1] in a light-independent
reaction. Upon exposure to visible light (300-500 nm), photolyase
absorbs a photon and transfers it into the cyclobutane ring, breaking the
bond and restoring the dipyrimidine monomers (reviewed in [2]). Although
yeast also express photolyase activity [3], it does not appear that human
cells contain a similar activity [4-6].
A second photolyase, which is specific for 6-4PPs has been reported in drosophila [7, 8] (reviewed in [9]). Although a human homologue for this photolyase does exist, it does not exhibit any detectable photolyase activity [10]. Similarly, the XPE protein appears to be a human photolyase homologue [11], without detectable photolyase activity. Rather its ability to recognise damaged DNA appears to have been incorporated into the damage recognition step of NER. |
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Glycosylases specific for UV-induced DNA damage
| The second distinct mechanism for the repairing UV-induced DNA damage is initiated by the product of the T4 bacteriophage gene endonuclease V (also called: T4N5, endoV, or denV). The product of the denV gene is a DNA glycosylase specific for CPDs, and contains apurinic/apyrimidinic lyase activities [12-14]. DenV acts by hydrolysing the 5'-glycosyl bond of a CPD. The resulting apyrimidinic site can be acted on by either an AP endonuclease or denV's own AP lyase activity, providing a substrate for the base excision repair pathway. Thus incision of CPDs by denV allows the processing of these lesions to be "shunted" from the nucleotide excision repair pathway, through which they are normally processed, into the base excision repair pathway. |
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| References:
1. Brash, D.E., et al., Escherichia coli DNA photolyase reverses cyclobutane pyrimidine dimers but not pyrimidine-pyrimidone (6-4) photoproducts. J Biol Chem, 1985. 260(21): p. 11438-41. 2. Sancar, A., Structure and function of DNA photolyase. Biochemistry, 1994. 33(1): p. 2-9. 3. Sancar, G.B., F.W. Smith, and P.F. Heelis, Purification of the yeast PHR1 photolyase from an Escherichia coli overproducing strain and characterization of the intrinsic chromophores of the enzyme. J Biol Chem, 1987. 262(32): p. 15457-65. 4. Tanew, A., B. Ortel, and H. Honigsmann, UVA does not photoreactivate pyrimidine dimers in cultured human fibroblasts. Exp Dermatol, 1993. 2(4): p. 161-4. 5. Chao, C.C., Lack of DNA enzymatic photoreactivation in HeLa cell-free extracts. FEBS Lett, 1993. 336(3): p. 411-6. 6. Li, Y.F., S.T. Kim, and A. Sancar, Evidence for lack of DNA photoreactivating enzyme in humans. Proceedings of the National Academy of Sciences of the United States of America, 1993. 90(10): p. 4389-93. 7. Todo, T., et al., Non-mutagenic repair of (6-4)photoproducts by (6-4)photolyase purified from Drosophila melanogaster. Mutat Res, 1997. 385(2): p. 83-93. 8. Kim, S.T., et al., Characterization of (6-4) photoproduct DNA photolyase. Journal of Biological Chemistry, 1994. 269(11): p. 8535-40. 9. Zhao, X. and D. Mu, (6-4) photolyase: light-dependent repair of DNA damage. Histol Histopathol, 1998. 13(4): p. 1179-82. 10. Todo, T., et al., Characterization of a human homolog of (6-4) photolyase. Mutat Res, 1997. 384(3): p. 195-204. 11. Patterson, M. and G. Chu, Evidence that xeroderma pigmentosum cells from complementation group E are deficient in a homolog of yeast photolyase. Mol Cell Biol, 1989. 9(11): p. 5105-12. 12. Gordon, L.K. and W.A. Haseltine, Comparison of the cleavage of pyrimidine dimers by the bacteriophage T4 and Micrococcus luteus UV-specific endonucleases. J Biol Chem, 1980. 255(24): p. 12047-50. 13. Nakabeppu, Y., K. Yamashita, and M. Sekiguchi, Purification and characterization of normal and mutant forms of T4 endonuclease V. J Biol Chem, 1982. 257(5): p. 2556-62. 14. Dodson, M.L. and R.S. Lloyd, Structure-function studies of the T4
endonuclease V repair enzyme. Mutat Res, 1989. 218(2): p. 49-65.
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