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Molecular Insights into the Translesion Synthesis of Benzyl-Guanine from Molecular Dynamics Simulations: Structural Evidence of Mutagenic and Nonmutagenic Replication.
- Source :
-
Biochemistry [Biochemistry] 2017 Apr 04; Vol. 56 (13), pp. 1841-1853. Date of Electronic Publication: 2017 Mar 24. - Publication Year :
- 2017
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Abstract
- DNA can be damaged by many compounds in our environment, and the resulting damaged DNA is commonly replicated by translesion synthesis (TLS) polymerases. Because the mechanism and efficiency of TLS are affected by the type of DNA damage, obtaining information for a variety of DNA adducts is critical. However, there is no structural information for the insertion of a dNTP opposite an O6-dG adduct, which is a particularly harmful class of DNA lesions. We used molecular dynamics (MD) simulations to investigate structural and energetic parameters that dictate preferred dNTP insertion opposite O6-benzyl-guanine (Bz-dG) by DNA polymerase IV, a prototypical TLS polymerase. Specifically, MD simulations were completed on all possible ternary insertion complexes and ternary -1 base deletion complexes with different Bz-dG conformations. Our data suggests that the purines are unlikely to be inserted opposite anti- or syn-Bz-dG, and dTTP is unlikely to be inserted opposite syn-Bz-dG, because of changes in the active site conformation, including critical hydrogen-bonding interactions and/or reaction-ready parameters compared to natural dG replication. In contrast, a preserved active site conformation suggests that dCTP can be inserted opposite either anti- or syn-Bz-dG and dTTP can be inserted opposite anti-Bz-dG. This is the first structural explanation for the experimentally observed preferential insertion of dCTP and misincorporation of dTTP opposite Bz-dG. Furthermore, we provide atomic level insight into why Bz-dG replication does not lead to deletion mutations, which is in contrast with the replication outcomes of other adducts. These findings provide a basis for understanding the replication of related O6-dG adducts.
- Subjects :
- Catalytic Domain
DNA Damage
DNA Polymerase beta genetics
DNA Polymerase beta metabolism
Deoxyadenine Nucleotides chemistry
Deoxyadenine Nucleotides metabolism
Deoxycytosine Nucleotides chemistry
Deoxycytosine Nucleotides metabolism
Deoxyguanine Nucleotides metabolism
Escherichia coli chemistry
Escherichia coli enzymology
Escherichia coli genetics
Escherichia coli Proteins genetics
Escherichia coli Proteins metabolism
Guanine analogs & derivatives
Hydrogen Bonding
Molecular Dynamics Simulation
Mutagenesis
Protein Structure, Secondary
Protein Structure, Tertiary
Thymine Nucleotides chemistry
Thymine Nucleotides metabolism
Benzyl Compounds chemical synthesis
DNA Adducts chemistry
DNA Polymerase beta chemistry
DNA Repair
DNA Replication
Deoxyguanine Nucleotides chemistry
Escherichia coli Proteins chemistry
Guanine chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 56
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28290677
- Full Text :
- https://doi.org/10.1021/acs.biochem.6b01247