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http://www.callutheran.edu/BioDev/omm/muth/frames/muthtxt.htm
Jessica Carney (1), Nathan Silva (3) and David Marcey (2)
David Marcey 2001
I. Introduction II. MutH Structure III. Activation of MutH IV. Similarity to Restriction Endonucleases V. References
Note: This exhibit is best viewed if the cue buttons( ) are pressed in sequence and if the viewer does not independently manipulate the molecule on the left.
I. Introduction
Despite the remarkable fidelity with which DNA polymerases replicate DNA, errors occur with measurable frequencies. Although some errors lead to mutations that increase an organism's fitness, most mutations are deleterious. Selection has thus evolved complex systems to surveil the genome for mutations and DNA damage and to repair these defects. The MutH protein of Escherichia coli, a weak endonuclease, is one enzyme of a multimeric complex that works to repair base mismatches (with the exception of C-C pairs) and small insertion or deletion mismatches in strands differing in up to four nucleotides. Figure 1 depicts the role of MutH, MutS, and MutL in methyl-directed mismatch repair. Once MutS, another mismatch repair protein, recognizes an error and associates with MutL, the complex in turn activates the latent endonuclease activity of MutH. MutH cleaves on one side of the mismatch at a hemi-methylated (GATC) sequence. Depending on whether MutH cuts on the 5' or 3' side of the mismatch, either exonuclease VII or exonuclease I is employed (together with MutS, MutL, and helicase II) to remove a stretch of DNA between the MutH cut and the mismatch. Repair synthesis followed by ligation restores a wild type dsDNA sequence. Please reload molecule before proceeding to the next section.
ions is
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likely similar to that of the restriction endonuclease EcoRV, to which it shows structural homology . Glu45 of EcoRV has been shown to coordinate a Mg ion that is critical in catalysis . The analagous residue in MutH is Glu56, which forms a water-mediated hydrogen bond with Glu77 .
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V. References
Au, Karin G., Katherine Welsh, and Paul Modrich. 1992. Initiation of Methyl-Directed Mismatch Repair. The Journal of Biological Chemistry 267: 12142-12148. Ban, Changill, and Wei Yang. 1998. Structural basis for MutH activation in E. coli mismatch repair and relationship of MutH to restriction endonucleases. The EMBO Journal 17: 1526-1534. Grafstrom, Robert H., and Ronald H. Hoess. 1987. Nucleotide sequence of the Escherichia coli mutH gene. Nucleic Acids Research 15: 3073-3084. Lahue, R.S., K.G. Au, and P. Modrich. 1989. DNA mismatch correction in a defined system. Nature 245: 160-164. Lahue, Robert S., and Paul Modrich. 1988. Methyl-directed DNA mismatch repair in Escherichia coli. Mutation Research 198: 37-43. Modrich, Paul, and Robert Lahue. 1996. Mismatch Repair in Replication Fidelity, Genetic Recombination, and Cancer Biology. Annu. Rev. Biochem. 65:101-133. Pingoud, Alfred, and Albert Jeltsch. Recognition and cleavage of DNA by type-II restriction endonucleases. Eur. J. Biochem. 246: 1-22. Rewinski, Caroline, M.G. Marinus. 1987. Mutation spectrum in Escherichia coli DNA mismatch repair deficient (mutH) strain. Nucleic Acids Research 15: 8205-8215. Smith, Jane, and Paul Modrich. 1996. Mutation detection with MutH, MutL, and MutS mismatch repair proteins. Proc.
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1. Kenyon College, Gambier, Ohio. A first draft of this exhibit was created for D. Marcey's Molecular Biology class, Biology 63. 2. California Lutheran University. Address correspondence to this author (see below). 3. California Lutheran University
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