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Genetics, Vol. 162, 1003-1018, November 2002, Copyright © 2002

Dissecting the Fidelity of Bacteriophage RB69 DNA Polymerase: Site-Specific Modulation of Fidelity by Polymerase Accessory Proteins

Anna Bebeneka,c, Geraldine T. Carvera, Holly Kloos Dressmana, Farid A. Kadyrova, Joseph K. Hasemanb, Vasiliy Petrovd, William H. Konigsberge, Jim D. Karamd, and John W. Drakea
a Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709-2233,
b Biometry Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709-2233,
c Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland,
d Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699
e Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06510-3219

Corresponding author: John W. Drake, Room E-344, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709-2233., drake{at}niehs.nih.gov (E-mail)

Communicating editor: S. LOVETT

Bacteriophage RB69 encodes a replicative B-family DNA polymerase (RB69 gp43) with an associated proofreading 3' exonuclease. Crystal structures have been determined for this enzyme with and without DNA substrates. We previously described the mutation rates and kinds of mutations produced in vivo by the wild-type (Pol+ Exo+) enzyme, an exonuclease-deficient mutator variant (Pol+ Exo-), mutator variants with substitutions at Tyr567 in the polymerase active site (PolM Exo+), and the double mutator PolM Exo-. Comparing the mutational spectra of the Pol+ Exo- and Pol+ Exo+ enzymes revealed the patterns and efficiencies of proofreading, while Tyr567 was identified as an important determinant of base-selection fidelity. Here, we sought to determine how well the fidelities of the same enzymes are reflected in vitro. Compared to their behavior in vivo, the three mutator polymerases exhibited modestly higher mutation rates in vitro and their mutational predilections were also somewhat different. Although the RB69 gp43 accessory proteins exerted little or no effect on total mutation rates in vitro, they strongly affected mutation rates at many specific sites, increasing some rates and decreasing others.




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