Sequence dependence of DNA conformational flexibility

Sarai, Akinori; Mazur, J.; Nussinov, Ruth; Jernigan, Robert L.

doi:10.1021/bi00445a046

Cited by 131 publications

(109 citation statements)

References 32 publications

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“…The comparison revealed similarities (Ͼ95%) among short sequences within the regions with high flexibility. These sequences are AϩT-rich, as expected from the flexibility value for this dinucleotide (25). Thus, these short sequence elements might be associated with the fragility of both FRA7H and FRA3B.…”

mentioning

confidence: 84%

“…In rare fragile sites the expanded CGG repeats affect helix flexibility, leading to repression of nucleosome assembly, decondensation, and fragility (34,35). Accordingly, we first searched the FRA7H sequence for potential local variations in the DNA flexibility, which appears to play an important role in protein-DNA interactions and hence might affect chromatin condensation (25). The analysis revealed four regions with potential high flexibility deviating significantly (Ͼ4.5 SD, based on the value of the lowest region among the four) from the average value of the entire FRA7H sequence (x ϭ 10.7°; SD ϭ 0.65; P Ͻ 0.0001) (Fig.…”

Section: Genetics: Mishmar Et Almentioning

confidence: 99%

“…The flexibility parameter that we used measured potential local variations in the DNA structure, expressed as fluctuations in the twist angle (25). The analysis was performed in overlapping windows of 100 bp.…”

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confidence: 99%

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Molecular characterization of a common fragile site ( FRA7H ) on human chromosome 7 by the cloning of a simian virus 40 integration site

Rahat

Scherer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Common fragile sites are chromosomal loci prone to breakage and rearrangement, hypothesized to provide targets for foreign DNA integration. We cloned a simian virus 40 integration site and showed by f luorescent in situ hybridization analysis that the integration event had occurred within a common aphidicolin-induced fragile site on human chromosome 7, FRA7H. A region of 161 kb spanning FRA7H was defined and sequenced. Several regions with a potential unusual DNA structure, including high-f lexibility, lowstability, and non-B-DNA-forming sequences were identified in this region. We performed a similar analysis on the published FRA3B sequence and the putative partial FRA7G, which also revealed an impressive cluster of regions with high f lexibility and low stability. Thus, these unusual DNA characteristics are possibly intrinsic properties of common fragile sites that may affect their replication and condensation as well as organization, and may lead to fragility.

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mentioning

confidence: 84%

Section: Genetics: Mishmar Et Almentioning

confidence: 99%

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Molecular characterization of a common fragile site ( FRA7H ) on human chromosome 7 by the cloning of a simian virus 40 integration site

Rahat

Scherer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

202

240

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“…The resulting set contained 1914 regions Flexibility is usually studied with FlexStab software (Mishmar et al, 1998). We implemented a similar algorithm using identical nucleotide-pair flexibility values (Sarai et al, 1989) to automate the whole-genome scanning process. Briefly, a region is divided into consecutive, potentially overlapping windows of user-defined length, as in the original FlexStab program.…”

Section: Allelic Imbalance Analysismentioning

confidence: 99%

“…Furthermore, the structural properties of the DNA molecule depend on the underlying nucleotide sequence (Sarai et al, 1989;Olson et al, 1998;Packer et al, 2000). For example, adenine-thymine pairs are generally considered more flexible than guanine-cytosine pairs.…”

Section: Introductionmentioning

confidence: 99%

Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study

et al. 2007

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Common fragile sites (CFSs) are regions of the genome prone to breakage by replication inhibitors (extrinsic replication stress). Recently, we and others observed that oncogene-induced replication stress (RS) induces DNA damage from the earliest stages of cancer. Our aim was to perform a genome-wide analysis in precancerous and cancerous experimental models to examine whether allelic imbalance occurs within CFSs. Subsequently, CFSs sequence characteristics were assessed. We used a growth-factor-induced human skin hyperplasia and a H-ras-induced mouse hyperplastic urothelium as preneoplastic models, along with an inducible U2OS-CDT1Tet-ON cancer cell line model, all bearing established oncogeneinduced RS stimuli. Human DNA was analysed with Affymetrix SNP microarrays, while mouse DNA was analysed with Nimblegen array CGH. We studied 56 aphidicolin-type CFSs and 1914 regions of control, nonfragile DNA. Our theoretical in silico analysis spanned 2.16 billion nonoverlapping bases on human chromosomes 1-22. Our results provide direct experimental evidence indicating that genomic alterations were more common within CFSs in epidermal and urothelial preneoplastic lesions as well as in cancer. CFSs were on average less flexible than nonfragile regions, contained more guanine-cytosine (GC) and Alu sequences. Importantly, regions with loss-of-heterozygosity were also less flexible and had a higher Alu percentage.

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Structure-based prediction of DNA target sites by regulatory proteins

1999

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Regulatory proteins play a critical role in controlling complex spatial and temporal patterns of gene expression in higher organism, by recognizing multiple DNA sequences and regulating multiple target genes. Increasing amounts of structural data on the protein-DNA complex provides clues for the mechanism of target recognition by regulatory proteins. The analyses of the propensities of base-amino acid interactions observed in those structural data show that there is no one-to-one correspondence in the interaction, but clear preferences exist. On the other hand, the analysis of spatial distribution of amino acids around bases shows that even those amino acids with strong base preference such as Arg with G are distributed in a wide space around bases. Thus, amino acids with many different geometries can form a similar type of interaction with bases. The redundancy and structural flexibility in the interaction suggest that there are no simple rules in the sequence recognition, and its prediction is not straightforward. However, the spatial distributions of amino acids around bases indicate a possibility that the structural data can be used to derive empirical interaction potentials between amino acids and bases. Such information extracted from structural databases has been successfully used to predict amino acid sequences that fold into particular protein structures. We surmised that the structures of protein-DNA complexes could be used to predict DNA target sites for regulatory proteins, because determining DNA sequences that bind to a particular protein structure should be similar to finding amino acid sequences that fold into a particular structure. Here we demonstrate that the structural data can be used to predict DNA target sequences for regulatory proteins. Pairwise potentials that determine the interaction between bases and amino acids were empirically derived from the structural data. These potentials were then used to examine the compatibility between DNA sequences and the protein-DNA complex structure in a combinatorial "threading" procedure. We applied this strategy to the structures of protein-DNA complexes to predict DNA binding sites recognized by regulatory proteins. To test the applicability of this method in target-site prediction, we examined the effects of cognate and noncognate binding, cooperative binding, and DNA deformation on the binding specificity, and predicted binding sites in real promoters and compared with experimental data. These results show that target binding sites for several regulatory proteins are successfully predicted, and our data suggest that this method can serve as a powerful tool for predicting multiple target sites and target genes for regulatory proteins.

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Sequence dependence of DNA conformational flexibility

Cited by 131 publications

References 32 publications

Molecular characterization of a common fragile site ( FRA7H ) on human chromosome 7 by the cloning of a simian virus 40 integration site

Molecular characterization of a common fragile site ( FRA7H ) on human chromosome 7 by the cloning of a simian virus 40 integration site

Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study

Structure-based prediction of DNA target sites by regulatory proteins

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