ArticleBiochemistry2010
Hinge residue I174 is critical for proper dNTP selection by DNA polymerase beta.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Article
- The Role of Natural Polymorphic Variants of DNA Polymerase β in DNA Repair.International journal of molecular sciences · 2022Review
- A pre-catalytic non-covalent step governs DNA polymerase β fidelity.Nucleic acids research · 2019Article
- I260Q DNA polymerase β highlights precatalytic conformational rearrangements critical for fidelity.Nucleic acids research · 2018Article
- DNA Polymerase β Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the β-γ Bridging Group of the Incoming dNTP.Biochemistry · 2017Article
- A Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant.Biochemistry · 2017Article
- DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy.Molecular cancer research : MCR · 2017Article
- Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer-Associated R438W DNA Polymerase Lambda Protein.Molecular cancer research : MCR · 2016Article
- Induced Fit in the Selection of Correct versus Incorrect Nucleotides by DNA Polymerase β.Biochemistry · 2016Article
- Fluorescence resonance energy transfer studies of DNA polymerase β: the critical role of fingers domain movements and a novel non-covalent step during nucleotide selection.The Journal of biological chemistry · 2014Article
- The S229L colon tumor-associated variant of DNA polymerase β induces cellular transformation as a result of decreased polymerization efficiency.The Journal of biological chemistry · 2014Article
- Biological and therapeutic relevance of nonreplicative DNA polymerases to cancer.Antioxidants & redox signaling · 2013Review
- Base excision repair and cancer.Cancer letters · 2012Review
- Catalytic effects of mutations of distant protein residues in human DNA polymerase β: theory and experiment.Biochemistry · 2012Article
- DNA polymerase β variant Ile260Met generates global gene expression changes related to cellular transformation.Mutagenesis · 2012Article
- Colon cancer-associated DNA polymerase β variant induces genomic instability and cellular transformation.The Journal of biological chemistry · 2012Article
- The E288K colon tumor variant of DNA polymerase β is a sequence specific mutator.Biochemistry · 2012Article
- Unfavorable electrostatic and steric interactions in DNA polymerase β E295K mutant interfere with the enzyme's pathway.Journal of the American Chemical Society · 2012Article
- A germline polymorphism of DNA polymerase beta induces genomic instability and cellular transformation.PLoS genetics · 2012Article
- A triad interaction in the fingers subdomain of DNA polymerase beta controls polymerase activity.Journal of the American Chemical Society · 2011Article
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Authors and funding
8 authors.
Funding
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 inserting a nucleotide opposite a template base G, and this loss of fidelity is due primarily to a loss of discrimination during ground state dNTP binding. Molecular dynamics simulations show that mutation of residue I174 to serine results in an overall tightening of the hinge region, resulting in aberrant protein dynamics and fidelity. These results point to the hinge region as being critical in the maintenance of the proper geometry of the dNTP binding pocket.
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