OF WORK: Through studies of RT's mechanism, our laboratory, in collaboration with Dr. Kunkel's laboratory and others, discovered that the mutation propensity is linked to how strongly the enzyme stays attached to the DNA template during replication. Thus, if RT falls off the viral template during replication, RT tends to make an error (or mutation) at the point where it climbs back on the template and continues replication. This mechanism appears to account for a portion of the HIV-1 genetic hypervariability. Much insight into the mechanism of """"""""falling off"""""""" has been gained by combining structural information on RT with biochemical studies of the wild-type enzyme and enzymes altered in specific amino acid residues that control affinity of binding to the template. Future work emphasizes the role DNA structure plays in the key polymerase function of selection of the correct nucleotide for insertion into the growing DNA strand. We are studying the roles of amino acids that make contact with the template base and incoming nucleotide, especially R72, and the surrounding amino acids.
| Shock, David D; Freudenthal, Bret D; Beard, William A et al. (2017) Modulating the DNA polymerase ? reaction equilibrium to dissect the reverse reaction. Nat Chem Biol 13:1074-1080 |
| Howard, Michael J; Wilson, Samuel H (2017) Processive searching ability varies among members of the gap-filling DNA polymerase X family. J Biol Chem 292:17473-17481 |
| Freudenthal, Bret D; Beard, William A; Cuneo, Matthew J et al. (2015) Capturing snapshots of APE1 processing DNA damage. Nat Struct Mol Biol 22:924-31 |
| Freudenthal, Bret D; Beard, William A; Perera, Lalith et al. (2015) Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide. Nature 517:635-9 |
| Beard, William A; Shock, David D; Batra, Vinod K et al. (2014) Substrate-induced DNA polymerase ? activation. J Biol Chem 289:31411-22 |
| Wu, Sangwook; Beard, William A; Pedersen, Lee G et al. (2014) Structural comparison of DNA polymerase architecture suggests a nucleotide gateway to the polymerase active site. Chem Rev 114:2759-74 |
| Perera, Lalith; Beard, William A; Pedersen, Lee G et al. (2014) Applications of quantum mechanical/molecular mechanical methods to the chemical insertion step of DNA and RNA polymerization. Adv Protein Chem Struct Biol 97:83-113 |
| Chary, Parvathi; Beard, William A; Wilson, Samuel H et al. (2013) Inhibition of HIV-1 reverse transcriptase-catalyzed synthesis by intercalated DNA Benzo[a]Pyrene 7,8-Dihydrodiol-9,10-Epoxide adducts. PLoS One 8:e72131 |
| Freudenthal, Bret D; Beard, William A; Shock, David D et al. (2013) Observing a DNA polymerase choose right from wrong. Cell 154:157-68 |
| Mueller, Geoffrey A; Pedersen, Lars C; Lih, Fred B et al. (2013) The novel structure of the cockroach allergen Bla g 1 has implications for allergenicity and exposure assessment. J Allergy Clin Immunol 132:1420-6 |
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