Oxidative DNA damage is produced endogenously by wayward free radicals from normal metabolism and exogenously by inflammation. Oxidative DNA damage is repaired by a system called base excision repair which is conserved from bacteria to humans. Oxidatively damaged DNA bases are recognized by enzymes called DNA glycosylases which catalyze the first step in the base excision repair process. The oxidative DNA glycosylases are members of two structural families, the HhH superfamily and the Fpg/Nei family. The former appear to be housekeeping genes that scan DNA looking for pyrimidine and purine damages, while the latter appear to have more specialized functions. In my talk I shall concentrate on the Fpg/Nei family and discuss the evolution of their substrate preferences from the founding member of the family, formamidopyrimidine DNA glycosylase (Fpg) to the human homologs, NEIL1, 2 and 3 (Nei-like). The functional substrate preferences will be correlated with structural features of the proteins. Some of our newer work with mouse Neil3 will be discussed showing it to prefer the further oxidation products of 8-oxoguanine, spiroiminodihydantoin and guanidinohydantoin, in single-stranded and double-stranded DNA, as well as lesions in quadruplex structures and telomeric sequence contexts. Finally our recent single molecule studies, showing that the bacterial oxidative DNA glycosylases of both families employ one dimensional diffusion to rotationally scan the DNA for damage using a wedge residue to detect deformities in the DNA backbone, will be discussed.
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Kathe, S.D., Barrantes-Reynolds, R., Bandaru, V., Bond, J.P. and Wallace, S.S. (2009) Plant and fungal Fpg homologs are formamidopyrimidine DNA glycosylases but not 8-oxoguanine DNA glycosylases. DNA Repair 8(5):643-53.
Liu, M., Bandaru, V., Bond, J.P., Jaruga, P., Zhao, X., Christov, P.O., Burrows, C.J, Rizzo, C.J., Dizdaroglu, M., and Wallace, S.S. (2010) The mouse ortholog of NEIL3 if a functional DNA glycosylase in vitro and in vivo. Proceedings National Academy of Sciences USA. 107(11):4925-30. PMCID: PMC2841873
Dunn, A.R., Kad, N.M., Nelso, S.R., Warshaw, D.M. and Wallace, S.S. (2011) Single Qdot-labeled glycosylase molecules use a wedge amino acid to probe for lesions while scanning along DNA. Jun 11. [Epub ahead of print, Open Access]