Reduced frameshift fidelity and processivity of HIV-1 reverse transcriptase mutants containing alanine substitutions in helix H of the thumb subdomain.

The Journal of Biological Chemistry
K BebenekT A Kunkel

Abstract

We have analyzed two human immunodeficiency virus (HIV-1) reverse transcriptase mutants of helix H in the thumb subdomain suggested by x-ray crystallography to interact with the primer strand of the template-primer. These enzymes, G262A and W266A, were previously shown to have greatly elevated dissociation rate constants for template-primer and to be much less sensitive to inhibition by 3'-azidodeoxythymidine 5'-triphosphate. Here we describe their processivity and error specificity. The results reveal that: (i) both enzymes have reduced processivity and lower fidelity for template-primer slippage errors, (ii) they differ from each other in sequence-dependent termination of processive synthesis and in error specificity, and (iii) the magnitude of the mutator effect relative to wild-type enzyme for deletions in homopolymeric sequences decreases as the length of the run increases. Thus amino acid substitutions in a subdomain thought to interact with the duplex template-primer confer a strand slippage mutator phenotype to a replicative DNA polymerase. This suggests that interactions between specific amino acids and the primer stem at positions well removed from the active site are critical determinants of processivity and fidelity...Continue Reading

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Citations

Dec 11, 1999·Mutation Research·B S Strauss
Mar 1, 1997·Nature Structural Biology·K BebenekT A Kunkel
May 30, 2009·The Journal of Biological Chemistry·Rajesh KasiviswanathanWilliam C Copeland
Oct 9, 2012·The Journal of Biological Chemistry·Stuart F J Le Grice
Jun 10, 2009·The Journal of Antimicrobial Chemotherapy·César GarrigaUNKNOWN Spanish Group for the Study of Antiretroviral Drug Resistance
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Jan 6, 2004·Nucleic Acids Research·Dimitry Bosoy, Neal F Lue
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Jul 20, 2011·Antimicrobial Agents and Chemotherapy·Richard V FariasOscar Leon
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Mar 13, 2014·Nature Structural & Molecular Biology·Elżbieta NowakMarcin Nowotny
Nov 4, 2008·Biochemical and Biophysical Research Communications·Yong-Xiang WangYu-Mei Wen
Sep 12, 2012·Environmental and Molecular Mutagenesis·Beverly A Baptiste, Kristin A Eckert
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