Hinge residue I174 is critical for proper dNTP selection by DNA polymerase beta.

Biochemistry
Jen YamtichJoann B Sweasy

Abstract

DNA polymerase beta (pol beta) is the key gap-filling polymerase in base excision repair, the DNA repair pathway responsible for repairing up to 20000 endogenous lesions per cell per day. Pol beta is also widely used as a model polymerase for structure and function studies, and several structural regions have been identified as being critical for the fidelity of the enzyme. One of these regions is the hydrophobic hinge, a network of hydrophobic residues located between the palm and fingers subdomains. Previous work by our lab has shown that hinge residues Y265, I260, and F272 are critical for polymerase fidelity by functioning in discrimination of the correct from incorrect dNTP during ground state binding. Our work aimed to elucidate the role of hinge residue I174 in polymerase fidelity. To study this residue, we conducted a genetic screen to identify mutants with a substitution at residue I174 that resulted in a mutator polymerase. We then chose the mutator mutant I174S for further study and found that it follows the same general kinetic pathway as and has an overall protein folding similar to that of wild-type (WT) pol beta. Using single-turnover kinetic analysis, we found that I174S exhibits decreased fidelity when insertin...Continue Reading

References

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Citations

Dec 2, 1999·Vaccine·M C RousseauJ Delmont
Apr 2, 2011·Journal of the American Chemical Society·Drew L MurphyJoann B Sweasy
May 11, 2012·The Journal of Biological Chemistry·Antonia A NemecJoann B Sweasy
Jul 17, 2012·Antioxidants & Redox Signaling·Jason L ParsonsRicky A Sharma
Oct 20, 2010·Seminars in Cancer Biology·Antonia A NemecJoann B Sweasy
Jan 19, 2012·Cancer Letters·Susan S WallaceJoann B Sweasy
Nov 17, 2019·Nucleic Acids Research·Khadijeh S AlnajjarJoann B Sweasy
Sep 11, 2020·Journal of Biomolecular Structure & Dynamics·Ahmed L Alaofi
Jan 12, 2017·Molecular Cancer Research : MCR·Antonia A NemecJoann B Sweasy

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