Molecular Dynamics Study of the Role of the Spine of Hydration in DNA A-Tracts in Determining Nucleosome Occupancy

Zhu, Xiao; Schatz, George C.

doi:10.1021/jp3084887

Cited by 18 publications

(15 citation statements)

References 62 publications

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“…This tendency of the probe to have increased emission intensity with an increase in the glycerol content clearly suggests that the restriction of intramolecular rotation is responsible for the fluorescence enhancement of QCy–DT . Consequently, the observed strong fluorescence enhancement in the presence of AT-rich DNA duplexes is the result of restriction of intramolecular rotation of probe QCy–DT in the constrained environments of DNA, which also facilitates the desolvation (water molecules) around QCy–DT in the hydrophobic environment of DNA duplex (Figure 1C ) ( 10 , 46 , 47 ). These preliminary results, thus, confirmed switch-on NIR-fluorescence behavior of QCy–DT in the presence of AT-rich DNA duplexes compared to that of GC-rich DNA duplex, ssDNAs and RNA.…”

Section: Resultsmentioning

confidence: 99%

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

et al. 2015

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In molecular biology, understanding the functional and structural aspects of DNA requires sequence-specific DNA binding probes. Especially, sequence-specific fluorescence probes offer the advantage of real-time monitoring of the conformational and structural reorganization of DNA in living cells. Herein, we designed a new class of D2A (one-donor-two-acceptor) near-infrared (NIR) fluorescence switch-on probe named quinone cyanine–dithiazole (QCy–DT) based on the distinctive internal charge transfer (ICT) process for minor groove recognition of AT-rich DNA. Interestingly, QCy–DT exhibited strong NIR-fluorescence enhancement in the presence of AT-rich DNA compared to GC-rich and single-stranded DNAs. We show sequence-specific minor groove recognition of QCy–DT for DNA containing 5′-AATT-3′ sequence over other variable (A/T)4 sequences and local nucleobase variation study around the 5′-X(AATT)Y-3′ recognition sequence revealed that X = A and Y = T are the most preferable nucleobases. The live cell imaging studies confirmed mammalian cell permeability, low-toxicity and selective staining capacity of nuclear DNA without requiring RNase treatment. Further, Plasmodium falciparum with an AT-rich genome showed specific uptake with a reasonably low IC50 value (<4 µM). The ease of synthesis, large Stokes shift, sequence-specific DNA minor groove recognition with switch-on NIR-fluorescence, photostability and parasite staining with low IC50 make QCy–DT a potential and commercially viable DNA probe.

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Section: Resultsmentioning

confidence: 99%

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

et al. 2015

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“…Direct repeats, and in particular A-tracts, displayed the strongest association with deletion breakpoints. A-tracts possess unique structural determinants, including the generation of static bending ( 89 – 91 ), a high degree of stiffness imparted by water coordination along the minor groove ( 92 , 93 ), directional narrowing of the minor groove ( 94 , 95 ), and flexible junctions, which appear to have been responsible for generating preferred sites for short (<200 bp) indels in the human population ( 95 ). A-tracts may form slipped structures as a result of misalignment during replication or transcription, as well as triplex DNA.…”

Section: Discussionmentioning

confidence: 99%

Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences

et al. 2016

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Gross chromosomal rearrangements (including translocations, deletions, insertions and duplications) are a hallmark of cancer genomes and often create oncogenic fusion genes. An obligate step in the generation of such gross rearrangements is the formation of DNA double-strand breaks (DSBs). Since the genomic distribution of rearrangement breakpoints is non-random, intrinsic cellular factors may predispose certain genomic regions to breakage. Notably, certain DNA sequences with the potential to fold into secondary structures [potential non-B DNA structures (PONDS); e.g. triplexes, quadruplexes, hairpin/cruciforms, Z-DNA and single-stranded looped-out structures with implications in DNA replication and transcription] can stimulate the formation of DNA DSBs. Here, we tested the postulate that these DNA sequences might be found at, or in close proximity to, rearrangement breakpoints. By analyzing the distribution of PONDS-forming sequences within ±500 bases of 19 947 translocation and 46 365 sequence-characterized deletion breakpoints in cancer genomes, we find significant association between PONDS-forming repeats and cancer breakpoints. Specifically, (AT)n, (GAA)n and (GAAA)n constitute the most frequent repeats at translocation breakpoints, whereas A-tracts occur preferentially at deletion breakpoints. Translocation breakpoints near PONDS-forming repeats also recur in different individuals and patient tumor samples. Hence, PONDS-forming sequences represent an intrinsic risk factor for genomic rearrangements in cancer genomes.

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“…MD simulations were performed as described ( 17 ). Briefly, we describe the interactions between DNA molecules and the environment (e.g.…”

Section: Methodsmentioning

confidence: 99%

Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes

Bacolla

Zhu²,

Chen

et al. 2015

Nucleic Acids Research

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Single base substitutions (SBSs) and insertions/deletions are critical for generating population diversity and can lead both to inherited disease and cancer. Whereas on a genome-wide scale SBSs are influenced by cellular factors, on a fine scale SBSs are influenced by the local DNA sequence-context, although the role of flanking sequence is often unclear. Herein, we used bioinformatics, molecular dynamics and hybrid quantum mechanics/molecular mechanics to analyze sequence context-dependent mutagenesis at mononucleotide repeats (A-tracts and G-tracts) in human population variation and in cancer genomes. SBSs and insertions/deletions occur predominantly at the first and last base-pairs of A-tracts, whereas they are concentrated at the second and third base-pairs in G-tracts. These positions correspond to the most flexible sites along A-tracts, and to sites where a ‘hole’, generated by the loss of an electron through oxidation, is most likely to be localized in G-tracts. For A-tracts, most SBSs occur in the direction of the base-pair flanking the tracts. We conclude that intrinsic features of local DNA structure, i.e. base-pair flexibility and charge transfer, render specific nucleotides along mononucleotide runs susceptible to base modification, which then yields mutations. Thus, local DNA dynamics contributes to phenotypic variation and disease in the human population.

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Molecular Dynamics Study of the Role of the Spine of Hydration in DNA A-Tracts in Determining Nucleosome Occupancy

Cited by 18 publications

References 62 publications

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

Sequence-specific recognition of DNA minor groove by an NIR-fluorescence switch-on probe and its potential applications

Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences

Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes

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