TY - JOUR
T1 - Antimutator variants of DNA polymerases
AU - Herr, Alan J.
AU - Williams, Lindsey N.
AU - Preston, Bradley D.
N1 - Funding Information:
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This work was supported by the National Institutes of Health (R01 ES09927, R01 CA098243, R01 CA111582, P20 CA103728, P30 AG13280, and P01 AG01751). Lindsey Williams was supported by a Public Health Service, National Research Service Award (T32 GM07270). Alan J. Herr, Ph.D., holds a Hitchings-Elion Fellowship from the Burroughs-Wellcome Fund (BWF 1000415.02).
PY - 2011/12
Y1 - 2011/12
N2 - Evolution balances DNA replication speed and accuracy to optimize replicative fitness and genetic stability. There is no selective pressure to improve DNA replication fidelity beyond the background mutation rate from other sources, such as DNA damage. However, DNA polymerases remain amenable to amino acid substitutions that lower intrinsic error rates. Here, we review these 'antimutagenic' changes in DNA polymerases and discuss what they reveal about mechanisms of replication fidelity. Pioneering studies with bacteriophage T4 DNA polymerase (T4 Pol) established the paradigm that antimutator amino acid substitutions reduce replication errors by increasing proofreading efficiency at the expense of polymerase processivity. The discoveries of antimutator substitutions in proofreading-deficient 'mutator' derivatives of bacterial Pols I and III and yeast Pol δ suggest there must be additional antimutagenic mechanisms. Remarkably, many of the affected amino acid positions from Pol I, Pol III, and Pol δ are similar to the original T4 Pol substitutions. The locations of antimutator substitutions within DNA polymerase structures suggest that they may increase nucleotide selectivity and/or promote dissociation of primer termini from polymerases poised for misincorporation, leading to expulsion of incorrect nucleotides. If misincorporation occurs, enhanced primer dissociation from polymerase domains may improve proofreading in cis by an intrinsic exonuclease or in trans by alternate cellular proofreading activities. Together, these studies reveal that natural selection can readily restore replication error rates to sustainable levels following an adaptive mutator phenotype.
AB - Evolution balances DNA replication speed and accuracy to optimize replicative fitness and genetic stability. There is no selective pressure to improve DNA replication fidelity beyond the background mutation rate from other sources, such as DNA damage. However, DNA polymerases remain amenable to amino acid substitutions that lower intrinsic error rates. Here, we review these 'antimutagenic' changes in DNA polymerases and discuss what they reveal about mechanisms of replication fidelity. Pioneering studies with bacteriophage T4 DNA polymerase (T4 Pol) established the paradigm that antimutator amino acid substitutions reduce replication errors by increasing proofreading efficiency at the expense of polymerase processivity. The discoveries of antimutator substitutions in proofreading-deficient 'mutator' derivatives of bacterial Pols I and III and yeast Pol δ suggest there must be additional antimutagenic mechanisms. Remarkably, many of the affected amino acid positions from Pol I, Pol III, and Pol δ are similar to the original T4 Pol substitutions. The locations of antimutator substitutions within DNA polymerase structures suggest that they may increase nucleotide selectivity and/or promote dissociation of primer termini from polymerases poised for misincorporation, leading to expulsion of incorrect nucleotides. If misincorporation occurs, enhanced primer dissociation from polymerase domains may improve proofreading in cis by an intrinsic exonuclease or in trans by alternate cellular proofreading activities. Together, these studies reveal that natural selection can readily restore replication error rates to sustainable levels following an adaptive mutator phenotype.
KW - Cancer
KW - DNA replication fidelity
KW - Genetic adaptation
KW - Genetic instability
KW - Mutator
KW - Protein structure/function
UR - http://www.scopus.com/inward/record.url?scp=81855169666&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=81855169666&partnerID=8YFLogxK
U2 - 10.3109/10409238.2011.620941
DO - 10.3109/10409238.2011.620941
M3 - Review article
C2 - 21977975
AN - SCOPUS:81855169666
SN - 1040-9238
VL - 46
SP - 548
EP - 570
JO - Critical Reviews in Biochemistry and Molecular Biology
JF - Critical Reviews in Biochemistry and Molecular Biology
IS - 6
ER -