Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies
DNA adducts, which block replicative DNA polymerases (DNAPs), are often bypassed by lesion-bypass DNAPs, which are mostly in the Y-Family. Y-Family DNAPs can do non-mutagenic or mutagenic dNTP insertion, and understanding this difference is important, because mutations transform normal into tumorige...
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| Format: | Article |
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Wiley
2010-01-01
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| Series: | Journal of Nucleic Acids |
| Online Access: | http://dx.doi.org/10.4061/2010/784081 |
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| author | Sushil Chandani Christopher Jacobs Edward L. Loechler |
| author_facet | Sushil Chandani Christopher Jacobs Edward L. Loechler |
| author_sort | Sushil Chandani |
| collection | DOAJ |
| description | DNA adducts, which block replicative DNA polymerases (DNAPs), are often bypassed by lesion-bypass DNAPs, which are mostly in the Y-Family. Y-Family DNAPs can do non-mutagenic or mutagenic dNTP insertion, and understanding this difference is important, because mutations transform normal into tumorigenic cells. Y-Family DNAP architecture that dictates mechanism, as revealed in structural and modeling studies, is considered. Steps from adduct blockage of replicative DNAPs, to bypass by a lesion-bypass DNAP, to resumption of synthesis by a replicative DNAP are described. Catalytic steps and protein conformational changes are considered. One adduct is analyzed in greater detail: the major benzo[a]pyrene adduct (B[a]P-N2-dG), which is bypassed non-mutagenically (dCTP insertion) by Y-family DNAPs in the IV/𝜅-class and mutagenically (dATP insertion) by V/𝜂-class Y-Family DNAPs. Important architectural differences between IV/𝜅-class versus V/𝜂-class DNAPs are discussed, including insights gained by analyzing ~400 sequences each for bacterial DNAPs IV and V, along with sequences from eukaryotic DNAPs kappa, eta and iota. The little finger domains of Y-Family DNAPs do not show sequence conservation; however, their structures are remarkably similar due to the presence of a core of hydrophobic amino acids, whose exact identity is less important than the hydrophobic amino acid spacing. |
| format | Article |
| id | doaj-art-afd44f5dae6f4913a2e63bdbe05c0989 |
| institution | Kabale University |
| issn | 2090-021X |
| language | English |
| publishDate | 2010-01-01 |
| publisher | Wiley |
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| series | Journal of Nucleic Acids |
| spelling | doaj-art-afd44f5dae6f4913a2e63bdbe05c09892025-08-20T03:39:14ZengWileyJournal of Nucleic Acids2090-021X2010-01-01201010.4061/2010/784081784081Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling StudiesSushil Chandani0Christopher Jacobs1Edward L. Loechler2Biology Department, Boston University, Boston, MA 02215, USAGraduate Program in Bioinformatics, Boston University, Boston, MA 02215, USABiology Department, Boston University, Boston, MA 02215, USADNA adducts, which block replicative DNA polymerases (DNAPs), are often bypassed by lesion-bypass DNAPs, which are mostly in the Y-Family. Y-Family DNAPs can do non-mutagenic or mutagenic dNTP insertion, and understanding this difference is important, because mutations transform normal into tumorigenic cells. Y-Family DNAP architecture that dictates mechanism, as revealed in structural and modeling studies, is considered. Steps from adduct blockage of replicative DNAPs, to bypass by a lesion-bypass DNAP, to resumption of synthesis by a replicative DNAP are described. Catalytic steps and protein conformational changes are considered. One adduct is analyzed in greater detail: the major benzo[a]pyrene adduct (B[a]P-N2-dG), which is bypassed non-mutagenically (dCTP insertion) by Y-family DNAPs in the IV/𝜅-class and mutagenically (dATP insertion) by V/𝜂-class Y-Family DNAPs. Important architectural differences between IV/𝜅-class versus V/𝜂-class DNAPs are discussed, including insights gained by analyzing ~400 sequences each for bacterial DNAPs IV and V, along with sequences from eukaryotic DNAPs kappa, eta and iota. The little finger domains of Y-Family DNAPs do not show sequence conservation; however, their structures are remarkably similar due to the presence of a core of hydrophobic amino acids, whose exact identity is less important than the hydrophobic amino acid spacing.http://dx.doi.org/10.4061/2010/784081 |
| spellingShingle | Sushil Chandani Christopher Jacobs Edward L. Loechler Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies Journal of Nucleic Acids |
| title | Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies |
| title_full | Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies |
| title_fullStr | Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies |
| title_full_unstemmed | Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies |
| title_short | Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies |
| title_sort | architecture of y family dna polymerases relevant to translesion dna synthesis as revealed in structural and molecular modeling studies |
| url | http://dx.doi.org/10.4061/2010/784081 |
| work_keys_str_mv | AT sushilchandani architectureofyfamilydnapolymerasesrelevanttotranslesiondnasynthesisasrevealedinstructuralandmolecularmodelingstudies AT christopherjacobs architectureofyfamilydnapolymerasesrelevanttotranslesiondnasynthesisasrevealedinstructuralandmolecularmodelingstudies AT edwardlloechler architectureofyfamilydnapolymerasesrelevanttotranslesiondnasynthesisasrevealedinstructuralandmolecularmodelingstudies |