Liu, Pingfang and Theruvathu, Jacob A. and Darwanto, Agus and Valinluck Lao, Victoria and Pascal, Tod and Goddard, William, III and Sowers, Lawrence C. (2008) Mechanisms of base selection by the E.coli mispaired uracil glycosylase. Journal of Biological Chemistry, 283 (14). pp. 8829-8836. ISSN 0021-9258 (In Press) http://resolver.caltech.edu/CaltechAUTHORS:LIUjbc08
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The repair of the multitude of single-base lesions formed daily in the cells of all living organisms is accomplished primarily by the base-excision repair (BER) pathway that initiates repair through a series of lesion-selective glycosylases. In this paper, single-turnover kinetics have been measured on a series of oligonucleotide substrates containing both uracil and purine analogs for the E. coli mispaired uracil glycosylase, MUG. The relative rates of glycosylase cleavage have been correlated with the free energy of helix formation, and with the size and electronic inductive properties of a series of uracil 5-substituents. Data is presented that MUG can exploit the reduced thermodynamic stability of mispairs to distinguish U:A from U:G pairs. Discrimination against the removal of thymine results primarily from the electron-donating property of the thymine 5-methyl substituent, while the size of the methyl group relative to a hydrogen atom is a secondary factor. A series of parameters have been obtained that allow prediction of relative MUG cleavage rates that correlate well with observed relative rates that vary over five orders of magnitude for the series of base analogs examined. We propose that these parameters may be common among DNA glycosylases, however, specific glycosylases may focus more or less on each of the parameters identified. The presence of a series of glycosylases which focus on different lesion properties, all coexisting within the same cell, would provide a robust and partially redundant repair system necessary for the maintenance of the genome.
|Additional Information:||Copyright © 2008 by the American Society for Biochemistry and Molecular Biology. Submitted on August 27, 2007. Revised on January 18, 2008. Accepted on January 20, 2008. Papers In Press, published online ahead of print January 20, 2008. This work was supported in part by National Institutes of Health Grants GM50351 and CA112293. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S11.|
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|Deposited On:||26 Feb 2008|
|Last Modified:||26 Dec 2012 09:51|
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