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At least 91 records · Page 5Linked to original sources
PubMed2000

Sequence analysis by additive scales: DNA structure for sequences and repeats of all lengths.

MOTIVATION: DNA structure plays an important role in a variety of biological processes. Different di- and tri-nucleotide scales have been proposed to capture various aspects of DNA structure including base stacking energy, propeller twist angle, protein deformability, bendability, and position preference. Yet, a general framework for the computational analysis and prediction of DNA structure is still lacking. Such a framework should in particular address the following issues: (1) construction of sequences with extremal properties; (2) quantitative evaluation of sequences with respect to a given genomic background; (3) automatic extraction of extremal sequences and profiles from genomic databases; (4) distribution and asymptotic behavior as the length N of the sequences increases; and (5) complete analysis of correlations between scales. RESULTS: We develop a general framework for sequence analysis based on additive scales, structural or other, that addresses all these issues. We show how to construct extremal sequences and calibrate scores for automatic genomic and database extraction. We show that distributions rapidly converge to normality as Nincreases. Pairwise correlations between scales depend both on background distribution and sequence length and rapidly converge to an analytically predictable asymptotic value. For di- and tri-nucleotide scales, normal behavior and asymptotic correlation values are attained over a characteristic window length of about 10-15 bp. With a uniform background distribution, pairwise correlations between empirically-derived scales remain relatively small and roughly constant at all lengths, except for propeller twist and protein deformability which are positively correlated. There is a positive (resp. negative) correlation between dinucleotide base stacking (resp. propeller twist and protein deformability) and AT-content that increases in magnitude with length. The framework is applied to the analysis of various DNA tandem repeats. We derive exact expressions for counting the number of repeat unit classes at all lengths. Tandem repeats are likely to result from a variety of different mechanisms, a fraction of which is likely to depend on profiles characterized by extreme structural features.

Animals↗
PubMed1998

DNA structural integrity and base composition affect ultraviolet light-induced oxidative DNA damage.

We previously demonstrated that ultraviolet (UV) light (254 nm) induced the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA via a singlet oxygen mechanism. In the present paper, we provide novel findings that DNA structure and base composition significantly affect the yield of 8-OHdG by UV radiation. Unlike ionizing radiation that induces 8-OHdG both in free 2'-deoxyguanosine (dG) and in DNA, UV light induced 8-OHdG formation in intact DNA and polydG.dC, but not in dG. When thermally denatured DNA was irradiated with UV light, the yield of 8-OHdG was reduced by more than 80% compared to intact DNA. Oxygenation of the denatured DNA solution did not restore the yield of UV-induced 8-OHdG. Irradiation of DNA with different AT/GC ratios showed that the yield of UV-induced 8-OHdG varied in proportion to the AT content, suggesting that AT base pairs in DNA enhance generation of the oxidizing species and subsequent oxidation of dG. The natural antioxidants genistein, estradiol, protocatechuic acid (PCA), and oleanolic acid (OA) were investigated for their inhibition of UV-induced 8-OHdG. Genistein and estradiol, that intercalate into DNA as shown by a computer modeling, significantly quenched UV-induced 8-OHdG, whereas PCA and OA did not fit into DNA and exhibited weak or no effect. These results suggest that the intercalation of genistein and estradiol into DNA may alter the DNA structural integrity, interrupt the production of oxidizing species, and subsequently reduce the formation of 8-OHdG by UV radiation.

Animals↗
PubMed1998

Computational applications of DNA structural scales.

We study from a computational standpoint several different physical scales associated with structural features of DNA sequences, including dinucleotide scales such as base stacking energy and propeller twist, and trinucleotide scales such as bendability and nucleosome positioning. We show that these scales provide an alternative or complementary compact representation of DNA sequences. As an example we construct a strand invariant representation of DNA sequences. The scales can also be used to analyze and discover new DNA structural patterns, especially in combinations with hidden Markov models (HMMs). The scales are applied to HMMs of human promoter sequences revealing a number of significant differences between regions upstream and downstream of the transcriptional start point. Finally we show, with some qualifications, that such scales are by and large independent, and therefore complement each other.

Artificial Intelligence↗
PubMed2006

The fission yeast DNA structure checkpoint protein Rad26ATRIP/LCD1/UVSD accumulates in the cytoplasm following microtubule destabilization.

BACKGROUND: DNA structure checkpoints are conserved eukaryotic signal transduction pathways that help preserve genomic integrity. Upon detecting checkpoint signals such as stalled replication forks or double-stranded DNA breaks, these pathways coordinate appropriate stress responses. Members of the PI-3 kinase related kinase (PIKK) family are essential elements of DNA structure checkpoints. In fission yeast, the Rad3 PIKK and its regulatory subunit Rad26 coordinate the detection of checkpoint signals with pathway outputs. RESULTS: We found that untreated rad26Delta cells were defective for two microtubule-dependent processes: chromosome segregation and morphogenesis. Interestingly, cytoplasmic accumulation of Rad26-GFP occurred following treatment with microtubule destabilizing drugs, but not during treatment with the genotoxic agent Phleomycin. Cytoplasmic accumulation of Rad26-GFP depended on Rad24, a 14-3-3 protein also required for DNA structure checkpoints and morphogenesis. Results of over expression and epistasis experiments confirm that Rad26 and Rad24 define a response to microtubule destabilizing conditions. CONCLUSION: Two DNA structure checkpoint proteins with roles in morphogenesis define a response to microtubule destabilizing conditions.

Actins↗
PubMed1995

DNA damage, mutation and fine structure DNA repair in aging.

The primary focus of this review is on correlations found between DNA damage, repair, and aging. New techniques for the measurement of DNA damage and repair at the level of individual genes, in individual DNA strands and in individual nucleotides will allow us to gain information regarding the nature of these correlations. Fine structure studies of DNA damage and repair in specific regions, including active genes, telomeres, and mitochondria have begun. Considerable intragenomic DNA repair heterogeneity has been found, and there have been indications of relationships between aging and repair in specific regions. More studies are necessary, however, particularly studies of the repair of endogenous damage. It is emphasized that the information obtained must be viewed from a perspective that takes into account the total responses of the cell to damaging events and the inter-relationships that exist between DNA repair and transcription.

Aging↗
PubMed1998

A novel unusual DNA structure formed in an inverted repeat sequence.

A potential to form a non-cruciform unusual DNA structure was shown at the inverted repeat DNA sequence of a fish satellite DNA. The recombinant plasmid harboring a member of the EcoRI satellite family of Sillago japonica (Percoidei, Sillaginidae) was subjected to S1 nuclease treatment, and the cutting sites were mapped by primer extension assay. The S1 nuclease attacked the 3'-half of the inverted repeat but not the middle part of symmetry under various salt conditions, suggesting that this unusual DNA structure is different from the DNA cruciform and a conventional intramolecular triplex structure. In the presence of 200 mM potassium chloride, the typical DNA cruciform has extruded, suggesting that certain purine-purine-pyrimidine base triads are involved in the formation of this unusual DNA structure. These results support the occurrence of a novel unusual DNA structure formed in the inverted repeat sequence.

Animals↗
PubMed1993

Parallel and antiparallel G-DNA structures from a complex telomeric sequence.

We investigated the formation in vitro of higher order structures by a DNA oligomer containing the terminal motif TGTG3TGTGTGTG3, derived from the Saccharomyces telomeric consensus, in order to (a) understand why certain cations favor the formation of parallel-stranded (G4 and G8) G-DNA structures, while others favor foldback, antiparallel structures (G'2) and (b) probe the structures of G-DNAs formed by this telomeric sequence, which is more complex than its well-studied counterparts from the protozoans oxytricha and tetrahymena. We find that dramatic switches in the formation of G4 versus G'2 structures occur in solutions of not only the group Ia cations, Li(+)-Cs+, but also in those of the group IIa cations, Mg(2+)-Ba2+. These data and the temperature-dependent formation and destruction of the different structures lend support to the kinetic scheme of Sen and Gilbert (1990), by which rapidly forming G'2 structures accumulate in highly stabilizing potassium (and strontium) solutions at the expense of the thermodynamically more stable G4 structures. Both the G4 and the G'2 complexes formed by the Saccharomyces sequence show novel structural features. Protection and interference experiments with dimethyl sulfate and potassium permanganate reveal that the core of alternating thymines and guanines within the telomeric motif plays a critical role in the stabilization of the parallel G4 structure, but not of the antiparallel G'2. Very likely, in the G4 complex, this GT core forms a novel higher order arrangement of alternating G and T quartets, the latter possibly comparable to the U quartets described by Cheong and Moore (1992) in their NMR study of the higher order structure formed by rUG4U.

Base Sequence↗
PubMed1989

Unusual DNA structures at the integration site of an HIV provirus.

Supercoiled pHXBc2 DNA (containing the genome of the human immunodeficiency virus type 1 and human sequences) migrated more slowly than linear DNA in native and ethidium bromide agarose gel electrophoresis at 4.5 volts/cm, suggesting the presence of unusual DNA structures. S1 nuclease analysis of pHXBc2 revealed two S1 hypersensitive sites. Site I was located within a 25 bp direct repeat in host DNA 0.6 kB upstream from the 5' LTR. Site II was mapped 0.2 kB upstream from the vif gene start site. Sequence analysis showed that Site I sequences could assume different unusual DNA structures, whereas sequences at Site II could assume either slipped or H-DNA forms. Unusual DNA structures in host DNA may be associated with active chromatin regions and may favor proviral integration.

Base Sequence↗
PubMed2005

Elastic correlations in nucleosomal DNA structure.

The structure of DNA in the nucleosome core particle is studied using an elastic model that incorporates anisotropy in the bending energetics and twist-bend coupling. Using the experimentally determined structure of nucleosomal DNA [T. J. Richmond and C. A. Davey, Nature (London) 423, 145 (2003)], it is shown that elastic correlations exist between twist, roll, tilt, and stretching of DNA, as well as the distance between phosphate groups. The twist-bend coupling term is shown to be able to capture these correlations to a large extent, and a fit to the experimental data yields a new estimate of G = 25 nm for the value of the twist-bend coupling constant.

Computer Simulation↗
PubMed2005

Effect of DNA structure on the formation of collagen-DNA complex.

Using various types of DNAs prepared from plasmid DNA, complete double-stranded DNA (ds.DNA) with linear and cyclic forms and double-stranded DNA coexisting with single-stranded DNA (ss.DNA), the structure and fibrillogenesis of the collagen-DNA complex were investigated by means of turbidity, transmission electron microscopy, and confocal laser-scanning microscopy. The rate of fibrillogenesis of the collagen-DNA complex significantly depends on the DNA structure. The structure of the fibrils formed in the complexes showed a marked difference between the ds.DNA and ss.DNA complexes with collagen. Spatial distribution of the DNA and collagen in the complexes suggests that the characteristic collagen-DNA interaction depends on the DNA forms.

Biocompatible Materials↗
PubMed1992

A simple spectral-driven procedure for the refinement of DNA structures by NMR spectroscopy.

We have developed a simple and quantitative procedure (SPEDREF) for the refinement of DNA structures using experimental two-dimensional nuclear Overhauser effect (2D NOE) data. The procedure calculates the simulated 2D NOE spectrum using the full matrix relaxation method on the basis of a molecular model. The volume of all NOE peaks is measured and compared between the experimental and the calculated spectra. The difference of the experimental and simulated volumes is minimized by a conjugated gradient procedure to adjust the interproton distances in the model. An agreement factor (analogous to the crystallographic R-factor) is used to monitor the progress of the refinement. The procedure is an The agreement is considered to be complete when several parameters, including the R-factor, the energy associated with the molecule, the local conformation (as judged by the sugar pseudorotation), and the global conformation (as judged by the helical x-displacement), are refined to their respective convergence. With the B-DNA structure of d(CGATCG) as an example, we show that DNA structure may be refined to produce calculated NOE spectra that are in excellent agreement with the experimental 2D NOE spectra. This is judged to be effective by the low R-factor of approximately 15%. Moreover, we demonstrate that not only are NOE data very powerful in providing details of the local structure but, with appropriate weighting of the NOE constraints, the global structure of the DNA double helix can also be determined, even when starting with a grossly different model. The reliability and limitations of a DNA structure as determined by NMR spectroscopy are discussed.

Base Sequence↗
PubMed1996

An in-the-groove view of DNA structures in complexes with proteins.

DNA structures bound to transcription factors are studied by using the crystal coordinates of complexes. Structural characteristics which are found at the sites where a protein secondary structure, an alpha-helix or a beta-sheet binds, can be understood in terms of fitting of the concave surface of the DNA major groove and the convex surface of the protein secondary structure; the former changes, becoming narrower or wider so that it fits the latter. An alpha-helix, independent of which groove it binds to, tends to produce a narrow major groove and a wide minor groove. When the major groove becomes narrower, the DNA helix axis bends around the major groove. Bending of DNA, which is overall structural change, is achieved by changes in local parameters (in particular, the roll parameter) so that an intermediate feature, the groove, fits the protein surface.

Base Composition↗
PubMedDate not supplied

The migration anomaly of DNA fragments in polyacrylamide gels allows the detection of small sequence-specific DNA structure variations.

Curved DNA fragments have a reduced electrophoretic mobility in polyacrylamide gels. The retardation in gels is extremely sensitive to small structural variations which influence the DNA helix axis. This gel assay can also be used to detect very small structural variations in DNA sequences which are not curved: The noncurved sequences of interest can be combined with curved stretches in phase with the helix turn. Using such sequence constructions, even subtle influences on the DNA helix axis can be detected. Experiments of this kind allow the determination of a relative order of sequence-specific DNA twist and wedge angles.

Base Composition↗
PubMed1994

The non-B-DNA structure of d(CA/TG)n differs from that of Z-DNA.

Chemical probing of two predominantly alternating purine-pyrimidine d(CA/TG)n repeats led us to propose previously that in supercoiled plasmids these elements adopt a non-B-DNA structure distinct from that of Z-DNA formed by d(CG)n sequences. Here, we present further evidence supporting this contention. Reactivity with the conformation-sensitive reagent chloroacetaldehyde, which reacts with unpaired adenines and cytosines, was confined strictly to adenines in the d(CA/TG)n repeat. In contrast, only bases outside the d(CG)n repeat exhibited chloroacetaldehyde reactivity. Two-dimensional gel analysis of topoisomers containing d(CA/TG)n tracts with bases out of strict purine-pyrimidine alteration revealed multiple superhelical-dependent transitions to an alternative left-handed structure. Within individual plasmid molecules, these multiple transitions resulted from the stepwise conversion of contiguous segments of alternating purine-pyrimidine sequence, which are delimited by bases out of alternation, to the full-length alternative conformation. When the left-handed helices increased in length to include more bases out of alternation, the average helical pitch changed substantially to produce a less tightly wound left-handed helix. Overall, these data indicate that d(CA/TG)n tracts adopt a left-handed conformation significantly different from that of the canonical Z-DNA structure of d(CG)n sequences.

Acetaldehyde↗
PubMed1975

Formaldehyde as a probe of DNA structure. II. Reaction with endocyclic imino groups of DNA bases.

We describe the equilibrium and kinetic aspects of the formaldehyde reaction with the endocyclic imino groups of derivatives of thymine, uracil, and a series of halogenated uracils, as well as poly(uridylic acid) and poly(inosinic acid). The main results are: (i) the equilibrium constants for forming a hydroxymethyl adduct remain quite constant at about 2-2.5 (M-1) for all the compounds studied, independent of their pK; (ii) both forward and reverse rate constants with 5'-TMP are specific base catalyzed in the pH range of about 4-9; (iii) the response of the rate constants to temperature and to several solvent additives are measured; (iv) at neutral pH, for the series of pyrimidine compounds, a linear free energy relation is observed between the logarithm of both the forward and the reverse rate constant and the pK for deprotonation; (v) the unstructured polynucleotides, poly(U) and poly(I) react very similarly to their constituent monomers; (vi) a reaction mechanism is proposed; and (vii) some implications for polynucleotide studies are discussed. In an appendix, a method of spectral analysis is derived to obtain accurate estimates of the quite small equilibrium constants; this should be applicable to all similar two-component systems in which the final product is unobtainable, either by isolation or by saturation. Together with the results of the previous paper on the formaldehyde reaction with exocyclic amino groups (J. D. McGhee and P. H. von Hippel, preceding paper), these results form a reasonably comprehensive account of the basic chemical controls required to use formaldehyde as a quantitative probe of DNA structure.

Chemical Phenomena↗
PubMed2006

Terminal DNA structure and ATP influence binding parameters of the DNA-dependent protein kinase at an early step prior to DNA synapsis.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) regulates the non-homologous end-joining pathway of DNA double-strand break repair in mammalian cells. The ability of DNA-PKcs to sense and respond to different terminal DNA structures is postulated to be important for its regulatory function. It is unclear whether discrimination occurs at the time of formation of the initial protein-DNA complex or later, at the time of formation of a paired, or synaptic complex between opposing DNA ends. To gain further insight into the mechanism of regulation, we characterized the binding of DNA-PKcs to immobilized DNA fragments that cannot undergo synapsis. Results showed that DNA-PKcs strongly discriminates between different terminal structures at the time of initial complex formation. Although Ku protein stabilizes DNA-PKcs binding overall, it is not required for discrimination between terminal structures. Base mispairing, temperature and the presence of an interstrand linkage influence the stability of the initial complex in a manner that suggests a requirement for DNA unwinding, reminiscent of the 'open complex' model of RNA polymerase-promoter DNA interaction. ATP and a nonhydrolyzable ATP analog also influence the stability of the DNA-PKcs*DNA complex, apparently by an allosteric mechanism that does not require DNA-PKcs autophosphorylation.

Adenosine Triphosphate↗
PubMed1985

Cleavage of cruciform DNA structures by an activity from Saccharomyces cerevisiae.

Protein extracts from Saccharomyces cerevisiae have been fractionated to reveal a nuclease activity that cleaves cruciform structures in DNA. Negatively supercoiled plasmids that contain inverted repeats that are extruded into cruciform structures have been used as DNA substrates. The sites of cleavage of pColIR215 DNA are located within the extruded cruciform stems and are symmetrically opposed to each other across the cruciform junction. Neither relaxed duplex DNA nor single-stranded DNA serve as substrates. The native molecular weight of the activity was estimated to be approximately equal to 200,000 by gel filtration.

DNA, Bacterial↗