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Molecular basis of selectivity of nucleoside triphosphate incorporation opposite O6-benzylguanine by sulfolobus solfataricus DNA polymerase Dpo4: steady-state and pre-steady-state kinetics and x-ray crystallography of correct and incorrect pairing.
Eoff RL, Angel KC, Egli M, Guengerich FP
(2007) J Biol Chem 282: 13573-84
MeSH Terms: Archaeal Proteins, Base Pair Mismatch, Base Pairing, Crystallography, X-Ray, DNA Polymerase beta, DNA Replication, DNA, Archaeal, DNA-Directed DNA Polymerase, Deoxyribonucleotides, Guanine, HIV Reverse Transcriptase, Humans, Kinetics, Mass Spectrometry, Sulfolobus solfataricus
Show Abstract · Added March 5, 2014
Previous work has shown that Sulfolobus solfataricus DNA polymerase Dpo4-catalyzed bypass of O(6)-methylguanine (O(6)-MeG) proceeds largely in an accurate but inefficient manner with a "wobble" base pairing between C and O(6)-MeG (Eoff, R. L., Irimia, A., Egli, M., and Guengerich, F. P. (2007) J. Biol. Chem. 282, 1456-1467). We considered here the bulky lesion O(6)-benzylguanine (O(6)-BzG) in DNA and catalysis by Dpo4. Mass spectrometry analysis of polymerization products revealed that the enzyme bypasses and extends across from O(6)-BzG, with C the major product ( approximately 70%) and some T and A ( approximately 15% each) incorporated opposite the lesion. Steady-state kinetic parameters indicated that Dpo4 was 7-, 5-, and 27-fold more efficient at C incorporation opposite O(6)-BzG than T, A, or G, respectively. In transient state kinetic analysis, the catalytic efficiency was decreased 62-fold for C incorporation opposite O(6)-BzG relative to unmodified DNA. Crystal structures reveal wobble pairing between C and O(6)-BzG. Pseudo-"Watson-Crick" pairing was observed between T and O(6)-BzG. Two other structures illustrate a possible mechanism for the accommodation of a +1 frameshift in the Dpo4 active site. The overall effect of O(6)-BzG is to decrease the efficiency of bypass by roughly an order of magnitude in every case except correct bypass, where the effect is not as pronounced. By comparison, Dpo4 is more accurate but no more efficient than model replicative polymerases, such as bacteriophage T7(-) DNA polymerase and human immunodeficiency virus-1 reverse transcriptase in the polymerization past O(6)-MeG and O(6)-BzG.
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15 MeSH Terms
Mutagenic effect of cadmium on tetranucleotide repeats in human cells.
Slebos RJ, Li M, Evjen AN, Coffa J, Shyr Y, Yarbrough WG
(2006) Mutat Res 602: 92-9
MeSH Terms: Base Pair Mismatch, Cadmium, DNA Repair, Fibrosarcoma, Humans, Methylnitronitrosoguanidine, Microsatellite Repeats, Mutagens, Mutation, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
Cadmium is a human carcinogen that affects cell proliferation, apoptosis and DNA repair processes that are all important to carcinogenesis. We previously demonstrated that cadmium inhibits DNA mismatch repair (MMR) in yeast cells and in human cell-free extracts (H.W. Jin, A.B. Clark, R.J.C. Slebos, H. Al-Refai, J.A. Taylor, T.A. Kunkel, M.A. Resnick, D.A. Gordenin, Cadmium is a mutagen that acts by inhibiting mismatch repair, Nat. Genet. 34 (3) (2003) 326-329), but cadmium also inhibits DNA excision repair. For this study, we selected a panel of three hypermutable tetranucleotide markers (MycL1, D7S1482 and DXS981) and studied their suitability as readout for the mutagenic effects of cadmium. We used a clonal derivative of the human fibrosarcoma cell line HT1080 to assess mutation levels in microsatellites after cadmium and/or N-methyl-N-nitro-N-nitrosoguanidine (MNNG) exposure to study effects of cadmium in the presence or absence of base damage. Mutations were measured in clonally expanded cells obtained by limiting dilution after exposure to zero dose, 0.5 microM cadmium, 5 nM MNNG or a combination of 0.5 microM cadmium and 5 nM MNNG. Exposure of HT1080-C1 to cadmium led to statistically significant increases in microsatellite mutations, either with or without concurrent exposure to MNNG. A majority of the observed mutant molecules involved 4-nucleotide shifts consistent with DNA slippage mutations that are normally repaired by MMR. These results provide evidence for the mutagenic effects of low, environmentally relevant levels of cadmium in intact human cells and suggest that inhibition of DNA repair is involved.
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10 MeSH Terms
SNPNB: analyzing neighboring-nucleotide biases on single nucleotide polymorphisms (SNPs).
Zhang F, Zhao Z
(2005) Bioinformatics 21: 2517-9
MeSH Terms: Algorithms, Base Pair Mismatch, Base Sequence, Chromosome Mapping, Computer Graphics, Genome, Human, Humans, Molecular Sequence Data, Nucleotides, Polymorphism, Single Nucleotide, Sequence Alignment, Sequence Analysis, DNA, Software, User-Computer Interface
Show Abstract · Added March 5, 2014
UNLABELLED - SNPNB is a user-friendly and platform-independent application for analyzing Single Nucleotide Polymorphism NeighBoring sequence context and nucleotide bias patterns, and subsequently evaluating the effective SNP size for the bias patterns observed from the whole data. It was implemented by Java and Perl. SNPNB can efficiently handle genome-wide or chromosome-wide SNP data analysis in a PC or a workstation. It provides visualizations of the bias patterns for SNPs or each type of SNPs.
AVAILABILITY - SNPNB and its full description are freely available at http://bioinfo.vipbg.vcu.edu/SNPNB/
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14 MeSH Terms
Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl DNA Adduct of butadiene diol epoxide with deoxyguanosine: formation of a dA(anti).dG(anti) pairing interaction.
Scholdberg TA, Nechev LV, Merritt WK, Harris TM, Harris CM, Lloyd RS, Stone MP
(2005) Chem Res Toxicol 18: 145-53
MeSH Terms: Base Pair Mismatch, Butadienes, DNA Adducts, Deoxyadenosines, Epoxy Compounds, Glycols, Humans, Hydrogen Bonding, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, Oligodeoxyribonucleotides, Poly U, Protons
Show Abstract · Added May 29, 2014
The (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl (BDT) adduct arising from alkylation of adenine N6 by butadiene diol epoxide (BDE) was placed opposite a mismatched deoxyguanosine nucleotide in the complementary strand of the oligodeoxynucleotide 5'-d(CGGACXAGAAG)-3'.5'-d(CTTCTGGTCCG)-3'. This oligodeoxynucleotide contains codon 61 (underlined) of the human N-ras protooncogene. The BDT adduct was at the second position of codon 61, and this was named the ras61 S,S-BDT-(61,2) A.G adduct. NMR spectroscopy revealed the presence of two conformations of the adducted mismatched duplex. In the major conformation, the mismatched base pair X6.G17 was oriented in a "face-to-face" orientation, in which both the modified nucleotide X6 and its complement G17 were intrahelical and in the anti conformation about the glycosyl bond. Hydrogen bonding was suggested between X6 N1 and G17 N1H and between X6 N6H and G17 O6. The presence of the BDT moiety allowed formation of a stable A.G mismatch pair. The identity of the minor conformation could not be determined. If not repaired, the resulting mismatch pair would generate A-->C mutations, which have been associated with this adenine N6 BDT adduct [Carmical, J. R., Nechev, L. N., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Env. Mol. Mutagen. 35, 48-56].
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15 MeSH Terms
Structural basis for the dual coding potential of 8-oxoguanosine by a high-fidelity DNA polymerase.
Brieba LG, Eichman BF, Kokoska RJ, Doublié S, Kunkel TA, Ellenberger T
(2004) EMBO J 23: 3452-61
MeSH Terms: Bacteriophage T7, Base Pair Mismatch, Base Pairing, Catalytic Domain, Crystallography, X-Ray, DNA Replication, DNA-Directed DNA Polymerase, Deoxyadenine Nucleotides, Deoxycytidine, Guanosine, Macromolecular Substances, Models, Molecular, Molecular Structure, Recombinant Proteins, Static Electricity
Show Abstract · Added April 7, 2017
Accurate DNA replication involves polymerases with high nucleotide selectivity and proofreading activity. We show here why both fidelity mechanisms fail when normally accurate T7 DNA polymerase bypasses the common oxidative lesion 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8oG). The crystal structure of the polymerase with 8oG templating dC insertion shows that the O8 oxygen is tolerated by strong kinking of the DNA template. A model of a corresponding structure with dATP predicts steric and electrostatic clashes that would reduce but not eliminate insertion of dA. The structure of a postinsertional complex shows 8oG(syn).dA (anti) in a Hoogsteen-like base pair at the 3' terminus, and polymerase interactions with the minor groove surface of the mismatch that mimic those with undamaged, matched base pairs. This explains why translesion synthesis is permitted without proofreading of an 8oG.dA mismatch, thus providing insight into the high mutagenic potential of 8oG.
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15 MeSH Terms
Analysis of the effect of bulk at N2-alkylguanine DNA adducts on catalytic efficiency and fidelity of the processive DNA polymerases bacteriophage T7 exonuclease- and HIV-1 reverse transcriptase.
Choi JY, Guengerich FP
(2004) J Biol Chem 279: 19217-29
MeSH Terms: Alkylation, Bacteriophage T7, Base Pair Mismatch, Catalysis, DNA Adducts, Exodeoxyribonucleases, Guanine, HIV Reverse Transcriptase, HIV-1, Kinetics, Mutation, Substrate Specificity, Viral Proteins, Virus Replication
Show Abstract · Added March 5, 2014
The N-2 atom of guanine (G) is susceptible to modification by various carcinogens. Oligonucleotides with increasing bulk at this position were analyzed for fidelity and catalytic efficiency with the processive DNA polymerases human immunodeficiency virus, type 1, reverse transcriptase (RT), and bacteriophage T7 exonuclease(-) (T7(-)). RT and T7(-) effectively bypassed N(2)-methyl(Me)G and readily extended primers but were strongly blocked by N(2)-ethyl(Et)G, N(2)-isobutylG, N(2)-benzylG, and N(2)-methyl(9-anthracenyl)G. Steady-state kinetics of single nucleotide incorporation by RT and T7(-) showed a decrease of 10(3) in k(cat)/K(m) for dCTP incorporation opposite N(2)-MeG and a further large decrease opposite N(2)-EtG. Misincorporation frequency was increased 10(2)-10(3)-fold by a Me group and another approximately 10(3)-fold by an Et group. dATP was preferentially incorporated opposite bulky N(2)-alkylG molecules. N(2)-MeG attenuated the pre-steady-state kinetic bursts with RT and T7(-), and N(2)-EtG eliminated the bursts. Large elemental effects with thio-dCTP(alphaS) were observed with N(2)-EtG (6- and 72-fold decreases) but were much less with N(2)-MeG, indicating that the N(2)-Et group may affect the rate of the chemistry step (phosphodiester bond formation). Similar values of K(d(dCTP)) and K(d(DNA)) and k(off) rates of DNA substrates from RT and T7(-) indicate that ground-state binding and dissociation rates are not considerably affected by the bulk. We conclude that even a Me group at the guanine N-2 atom can cause a profound interfering effect on the fidelity and efficiency; an Et or larger group causes preferential misincorporation and strong blockage of replicative polymerases, probably at and before the chemistry step, demonstrating the role of bulk in DNA lesions.
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14 MeSH Terms
The N2-ethylguanine and the O6-ethyl- and O6-methylguanine lesions in DNA: contrasting responses from the "bypass" DNA polymerase eta and the replicative DNA polymerase alpha.
Perrino FW, Blans P, Harvey S, Gelhaus SL, McGrath C, Akman SA, Jenkins GS, LaCourse WR, Fishbein JC
(2003) Chem Res Toxicol 16: 1616-23
MeSH Terms: Animals, Base Pair Mismatch, Base Sequence, Cattle, DNA Adducts, DNA Damage, DNA Polymerase I, DNA Primers, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, Guanine, Humans, Kinetics, Mutagenesis, Insertional, Nucleotides, Oligonucleotides, Recombinant Proteins, Templates, Genetic, Thymus Gland
Show Abstract · Added January 27, 2012
The effects of N(2)-ethylGua, O(6)-ethylGua, and O(6)-methylGua adducts in template DNA on polymerization by mammalian DNA polymerases alpha and eta have been investigated. The N(2)-ethylGua adduct blocks polymerization by the replicative DNA polymerase alpha to a much greater extent than does the O(6)-ethyl- or the O(6)-methylGua adducts. The DNA polymerase eta efficiently and accurately bypasses the N(2)-ethylGua lesion but like DNA polymerase alpha is similarly blocked by the O(6)-ethyl- or the O(6)-methylGua adducts. A steady state kinetic analysis of nucleotide insertion opposite the N(2)-ethylGua and the O(6)-ethylGua adducts by the DNA polymerases alpha and eta and extension from 3'-termini positioned opposite these adducts was performed to measure the efficiency and the accuracy of DNA synthesis past these lesions. This analysis showed that insertion of Cyt opposite the N(2)-ethylGua adduct by DNA polymerase alpha is approximately 10(4)-fold less efficient than insertion of Cyt opposite an unadducted Gua residue at the same position. Extension from the N(2)-ethylGua:Cyt 3'-terminus by DNA polymerase alpha is approximately 10(3)-fold less efficient than extension from a Cyt opposite the unadducted Gua. Insertion of Cyt opposite the N(2)-ethylGua lesion by the DNA polymerase eta is about 370-fold more efficient than by the DNA polymerase alpha, and extension from the N(2)-ethylGua:Cyt 3'-terminus by the DNA polymerase eta is about 3-fold more efficient than by the DNA polymerase alpha. Furthermore, the DNA polymerase eta preferably inserts the correct nucleotide Cyt opposite the N(2)-ethylGua lesion with nearly the same level of accuracy as opposite an unadducted Gua, thus minimizing the mutagentic potential of this lesion. This result contrasts with the relatively high misincorporation efficiency of Thy opposite the O(6)-ethylGua adduct by the DNA polymerases alpha and eta. In reactions containing both DNA polymerases alpha and eta, synthesis past the N(2)-ethylGua adduct is detected to permit completed replication of the adducted oligonucleotide template. These results suggest that accurate replication past the N(2)-ethylGua adduct might be facilitated in cells by pausing of replication catalyzed by DNA polymerase alpha and lesion bypass catalyzed by DNA polymerase eta.
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20 MeSH Terms
Cadmium is a mutagen that acts by inhibiting mismatch repair.
Jin YH, Clark AB, Slebos RJ, Al-Refai H, Taylor JA, Kunkel TA, Resnick MA, Gordenin DA
(2003) Nat Genet 34: 326-9
MeSH Terms: Base Pair Mismatch, Cadmium, DNA Repair, DNA Replication, DNA, Fungal, DNA-Directed DNA Polymerase, Genome, Kinetics, Mitosis, Mutagens, Saccharomyces cerevisiae
Show Abstract · Added March 5, 2014
Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.
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11 MeSH Terms
Wobble dC.dA pairing 5' to the cationic guanine N7 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 adduct: implications for nontargeted AFB1 mutagenesis.
Giri I, Stone MP
(2003) Biochemistry 42: 7023-34
MeSH Terms: Aflatoxin B1, Base Composition, Base Pair Mismatch, Base Sequence, Cations, DNA Adducts, Deoxyadenine Nucleotides, Deoxycytosine Nucleotides, Guanine, Hydrogen-Ion Concentration, Intercalating Agents, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Nucleic Acid Conformation, Nucleic Acid Heteroduplexes, Oligodeoxyribonucleotides, Protons, Structure-Activity Relationship
Show Abstract · Added May 29, 2014
The structure of 5'-d(ACATC(AFB)GATCT)-3'.5'-d(AGATCAATGT)-3', containing the C(5).A(16) mismatch at the base pair 5' to the modified (AFB)G(6), was determined by NMR. The characteristic 5'-intercalation of the AFB(1) moiety was maintained. The mismatched C(5).A(16) pair existed in the wobble conformation, with the C(5) imino nitrogen hydrogen bonded to the A(16) exocyclic amino group. The wobble pair existed as a mixture of protonated and nonprotonated species. The pK(a) for protonation at the A(16) imino nitrogen was similar to that of the C(5).A(16) wobble pair in the corresponding duplex not adducted with AFB(1). Overall, the presence of AFB(1) did not interfere with wobble pair formation at the mismatched site. Molecular dynamics calculations restrained by distances derived from NOE data and torsion angles derived from (1)H (3)J couplings were carried out for both the protonated and nonprotonated wobble pairs at C(5).A(16). Both sets of calculations predicted the A(16) amino group was within 3 A of the C(5) imino nitrogen. The calculations suggested that protonation of the C(5).A(16) wobble pair should shift C(5) toward the major groove and shift A(16) toward the minor groove. The NMR data showed evidence for the presence of a minor conformation characterized by unusual NOEs between T(4) and (AFB)G(6). T(4) is two nucleotides in the 5'-direction from the modified base. These NOEs suggested that in the minor conformation nucleotide T(4) was in closer proximity to (AFB)G(6) than would be expected for duplex DNA. Modeling studies examined the possibility that T(4) transiently paired with the mismatched A(16), allowing it to come within NOE distance of (AFB)G(6). This model structure was consistent with the unusual NOEs associated with the minor conformation. The structural studies are discussed in relationship to nontargeted C --> T transitions observed 5' to the modified (AFB)G in site-specific mutagenesis experiments [Bailey, E. A., Iyer, R. S., Stone, M. P., Harris, T. M., and Essigmann, J. M. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 1535-1539].
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18 MeSH Terms
The inherent properties of DNA four-way junctions: comparing the crystal structures of holliday junctions.
Eichman BF, Ortiz-Lombardía M, Aymamí J, Coll M, Ho PS
(2002) J Mol Biol 320: 1037-51
MeSH Terms: Base Pair Mismatch, Computer Simulation, Crystallography, X-Ray, DNA, Deoxyribonucleotides, Models, Molecular, Nucleic Acid Conformation, Oligodeoxyribonucleotides, Solvents
Show Abstract · Added April 7, 2017
Holliday junctions are four-stranded DNA complexes that are formed during recombination and related DNA repair events. Much work has focused on the overall structure and properties of four-way junctions in solution, but we are just now beginning to understand these complexes at the atomic level. The crystal structures of two all-DNA Holliday junctions have been determined recently from the sequences d(CCGGGACCGG) and d(CCGGTACCGG). A detailed comparison of the two structures helps to distinguish distortions of the DNA conformation that are inherent to the cross-overs of the junctions in this crystal system from those that are consequences of the mismatched dG.dA base-pair in the d(CCGGGACCGG) structure. This analysis shows that the junction itself perturbs the sequence-dependent conformational features of the B-DNA duplexes and the associated patterns of hydration in the major and minor grooves only minimally. This supports the idea that a DNA four-way junction can be assembled at relatively low energetic cost. Both structures show a concerted rotation of the adjacent duplex arms relative to B-DNA, and this is discussed in terms of the conserved interactions between the duplexes at the junctions and further down the helical arms. The interactions distant from the strand cross-overs of the junction appear to be significant in defining its macroscopic properties, including the angle relating the stacked duplexes across the junction.
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9 MeSH Terms