Cited by 79DNA Repair MechanismsEnzyme Structure and FunctionProtein Structure and Dynamics

Structure-based interpretation of missense mutations in Y-family DNA polymerases and their implications for polymerase function and lesion bypass

Boudsocq, F·2002·DNA Repair

Abstract

Our understanding of the molecular mechanisms of error-prone lesion bypass has changed dramatically in the past few years. The concept that the key participants in the mutagenic process were accessory proteins that somehow modified the ability of the cell's main replicase to facilitate bypass of normally blocking lesions has been replaced with one in which the replicase is displaced by a polymerase specialized in lesion bypass. The participants in this process remain the same, only their function has been reassigned. What was once known as the UmuC/DinB/Rev1/Rad30 superfamily of mutagenesis proteins, is now known as the Y-family of DNA polymerases. Quite remarkably, within the space of 3 years, the field has advanced from the initial discovery of intrinsic polymerase function, to the determination of the tertiary structures of several Y-family DNA polymerases.A key to determining the biochemical properties of each DNA polymerase is through structure-function studies that result in the site-specific substitution of particular amino acids at critical sites within each DNA polymerase. However, we should not forget the power of genetic selection that allows us to identify residues within each polymerase that are generated by "random mutagenesis" and which are important for both a gain or loss of function in vivo. In this review, we discuss the structural ramifications of several missense mutations previously identified in various Y-family DNA polymerase and speculate on how each amino acid substitution might modify the enzymatic activity of the respective polymerase or possibly perturb protein-protein interactions necessary for efficient translesion replication in vivo.

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Crossref · 10.1016/s1568-7864(02)00019-8

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  • These ideas are supported by structural information and by a report that the insertion fidelity of yeast Pol η is severely impaired with difluorotoluene, a nonpolar isosteric analog of thymine that is unable to form Watson-Crick hydrogen bonds with adenine.

    “These ideas are supported by structural information (20, 21, 26 -28) and by a report (29) that the insertion fidelity of yeast Pol ␩ is severely impaired with difluorotoluene, a nonpolar isosteric analog of thymine that is unable to form Watson-Crick hydrogen bonds with adenine.”

    From DNA Replication Fidelity (2004) · cites this paper as [26]

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Authors
Boudsocq, F.
Affiliations
National Institutes of Health (US)
Corresponding author
Boudsocq, F
Venue
DNA Repair
Publisher
Elsevier BV
Published
2002-05-30
Volume
1
Issue
5
Pages
343-358
ISSN
  • 1568-7856 (ISSN-L)
  • 1568-7864
OpenAlex
W2056808794
Cited by
79
References
96
Citations by year
2026: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 8 · 2012: 6
FWCI
3.24
Type
journal article
Language
en
Open access
closed
Locations
  • DNA repair (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute for Health and Care Research
  • National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
Y-family DNA polymerases, missense mutations, translesion synthesis, error-prone DNA replication, lesion bypass, structure-function relationship, protein tertiary structure, amino acid substitutions, protein-protein interaction
MeSH terms
Amino Acid Sequence, Animals, DNA Damage, DNA-Directed DNA Polymerase, DNA Repair, DNA Replication, Escherichia coli, Multigene Family, Humans, Models, Genetic, Molecular Sequence Data, Protein Conformation, Structure-Activity Relationship, Sequence Homology, Amino Acid, Protein Folding, Amino Acid Substitution, Mutation, Missense

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