scholarly journals Topoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks

2020 ◽  
Vol 48 (12) ◽  
pp. 6654-6671
Author(s):  
Karol Szlachta ◽  
Arkadi Manukyan ◽  
Heather M Raimer ◽  
Sandeep Singh ◽  
Anita Salamon ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Human Genome ◽  
Topoisomerase Ii ◽  
Genome Instability ◽  
Secondary Structures ◽  
Ctcf Binding ◽  
Dna Secondary Structure ◽  
Disease Etiology ◽  
Dna Secondary Structures ◽  
Genomic Regions

Abstract DNA double-stranded breaks (DSBs) trigger human genome instability, therefore identifying what factors contribute to DSB induction is critical for our understanding of human disease etiology. Using an unbiased, genome-wide approach, we found that genomic regions with the ability to form highly stable DNA secondary structures are enriched for endogenous DSBs in human cells. Human genomic regions predicted to form non-B-form DNA induced gross chromosomal rearrangements in yeast and displayed high indel frequency in human genomes. The extent of instability in both analyses is in concordance with the structure forming ability of these regions. We also observed an enrichment of DNA secondary structure-prone sites overlapping transcription start sites (TSSs) and CCCTC-binding factor (CTCF) binding sites, and uncovered an increase in DSBs at highly stable DNA secondary structure regions, in response to etoposide, an inhibitor of topoisomerase II (TOP2) re-ligation activity. Importantly, we found that TOP2 deficiency in both yeast and human leads to a significant reduction in DSBs at structure-prone loci, and that sites of TOP2 cleavage have a greater ability to form highly stable DNA secondary structures. This study reveals a direct role for TOP2 in generating secondary structure-mediated DNA fragility, advancing our understanding of mechanisms underlying human genome instability.

Control of guanine-rich DNA secondary structures depending on the protease activity using a designed PNA peptide

2015 ◽  
Vol 13 (7) ◽  
pp. 2022-2025 ◽  
Author(s):  
Kenji Usui ◽  
Arisa Okada ◽  
Keita Kobayashi ◽  
Naoki Sugimoto
Keyword(s):  
Secondary Structure ◽  
Structure Formation ◽  
Protease Activity ◽  
Secondary Structures ◽  
Regulation System ◽  
Dna Secondary Structure ◽  
Secondary Structure Formation ◽  
Dna Secondary Structures

A regulation system for DNA secondary structure formation of G-rich sequences using a designed PNA peptide exhibiting an enzyme-responsive functionality, depending on the protease activity was constructed.

scholarly journals Single-cell mapping of DNA G-quadruplex structures in human cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Winnie W. I. Hui ◽  
Angela Simeone ◽  
Katherine G. Zyner ◽  
David Tannahill ◽  
Shankar Balasubramanian
Keyword(s):  
Secondary Structure ◽  
Single Cell ◽  
Genome Instability ◽  
Human Cancer ◽  
Single Cells ◽  
Dna Secondary Structure ◽  
Genomic Locus ◽  
Mixed Cell ◽  
Human Cancer Cell Lines ◽  
Human Cancer Cells

AbstractG-quadruplexes (G4s) are four-stranded DNA secondary structures that form in guanine-rich regions of the genome. G4s have important roles in transcription and replication and have been implicated in genome instability and cancer. Thus far most work has profiled the G4 landscape in an ensemble of cell populations, therefore it is critical to explore the structure–function relationship of G4s in individual cells to enable detailed mechanistic insights into G4 function. With standard ChIP-seq methods it has not been possible to determine if G4 formation at a given genomic locus is variable between individual cells across a population. For the first time, we demonstrate the mapping of a DNA secondary structure at single-cell resolution. We have adapted single-nuclei (sn) CUT&Tag to allow the detection of G4s in single cells of human cancer cell lines. With snG4-CUT&Tag, we can distinguish cellular identity from a mixed cell-type population solely based on G4 features within individual cells. Our methodology now enables genomic investigations on cell-to-cell variation of a DNA secondary structure that were previously not possible.

scholarly journals Rearrangements of theMLLgene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding

2009 ◽  
Vol 48 (9) ◽  
pp. 806-815 ◽  
Author(s):  
Hongan Le ◽  
Sheetal Singh ◽  
Shyh-Jen Shih ◽  
Nga Du ◽  
Sabine Schnyder ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Topoisomerase Ii ◽  
Dna Secondary Structure

scholarly journals Experimental Confirmation of Multiple Co-Existent DNA Secondary Structures using Low-Yield Bisulfite Sequencing

2021 ◽  
Author(s):  
Jiaming Li ◽  
Jin Bae ◽  
Boyan Yordanov ◽  
Michael X Wang ◽  
Javier Gonzalez ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Single Molecule ◽  
Dna Sequences ◽  
Bisulfite Sequencing ◽  
Secondary Structures ◽  
Single Molecule Level ◽  
Dna Oligonucleotides ◽  
Metastable Structures ◽  
Structure State ◽  
Dna Secondary Structures

The prediction of DNA secondary structures from DNA sequences using thermodynamic models is imperfect for many biological sequences, both due to insufficient experimental data for training and to the kinetics of folding that lead to metastable structures. Here, we developed low-yield bisulfite sequencing (LYB-seq) to query the secondary structure states of cytosine (C) nucleotides in thousands of different DNA oligonucleotides on a single-molecule level. We observed that the reaction kinetics between bisulfite and C nucleotides is highly dependent on the secondary structure state of the C nucleotides, with the most accessible C nucleotides (those in small hairpin loops) reacting 70-fold faster than those in stable duplexes. Next, we developed a statistical model to evaluate the likelihood of an NGS read being consistent with a particular proposed secondary structure. By analyzing thousands of NGS reads for each DNA species, we can infer the distribution of secondary structures adopted by each species in solution. We find that 84% of 1,057 human genome subsequences studied here adopt 2 or more stable secondary structures in solution.

scholarly journals Evolutionary analyses of base-pairing interactions in DNA and RNA secondary structures

2018 ◽  
Author(s):  
Michael Golden ◽  
Ben Murrell ◽  
Oliver G. Pybus ◽  
Darren Martin ◽  
Jotun Hein
Keyword(s):  
Secondary Structure ◽  
Secondary Structures ◽  
Sequence Evolution ◽  
Base Pairing ◽  
Sequence Alignments ◽  
Dna Viruses ◽  
Dna And Rna ◽  
Subtype B ◽  
Dna Secondary Structures ◽  
Hiv 1

AbstractPairs of nucleotides within functional nucleic acid secondary structures often display evidence of coevolution that is consistent with the maintenance of base-pairing. Here we introduce a sequence evolution model, MESSI, that infers coevolution associated with base-paired sites in DNA or RNA sequence alignments. MESSI can estimate coevolution whilst accounting for an unknown secondary structure. MESSI can also use GPU parallelism to increase computational speed. We used MESSI to infer coevolution associated with GC, AU (AT in DNA), GU (GT in DNA) pairs in non-coding RNA alignments, and in single-stranded RNA and DNA virus alignments. Estimates of GU pair coevolution were found to be higher at base-paired sites in single-stranded RNA viruses and non-coding RNAs than estimates of GT pair coevolution in single-stranded DNA viruses, suggesting that GT pairs do not stabilise DNA secondary structures to the same extent that GU pairs do in RNA. Additionally, MESSI estimates the degrees of coevolution at individual base-paired sites in an alignment. These estimates were computed for a SHAPE-MaP-determined HIV-1 NL4-3 RNA secondary structure and two corresponding alignments. We found that estimates of coevolution were more strongly correlated with experimentally-determined SHAPE-MaP pairing scores than three non-evolutionary measures of base-pairing covariation. To assist researchers in prioritising substructures with potential functionality, MESSI automatically ranks substructures by degrees of coevolution at base-paired sites within them. Such a ranking was created for an HIV-1 subtype B alignment, revealing an excess of top-ranking substructures that have been previously identified as having structure-related functional importance, amongst several uncharacterised top-ranking substructures.

scholarly journals Structural relation matching: an algorithm to identify structural patterns into RNAs and their interactions

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Michela Quadrini
Keyword(s):  
Hydrogen Bonding ◽  
Secondary Structure ◽  
Nucleotide Sequence ◽  
Thermus Thermophilus ◽  
Three Dimensional ◽  
Secondary Structures ◽  
Structural Effect ◽  
Biological Processes ◽  
Structural Pattern ◽  
Rna Molecules

Abstract RNA molecules play crucial roles in various biological processes. Their three-dimensional configurations determine the functions and, in turn, influences the interaction with other molecules. RNAs and their interaction structures, the so-called RNA–RNA interactions, can be abstracted in terms of secondary structures, i.e., a list of the nucleotide bases paired by hydrogen bonding within its nucleotide sequence. Each secondary structure, in turn, can be abstracted into cores and shadows. Both are determined by collapsing nucleotides and arcs properly. We formalize all of these abstractions as arc diagrams, whose arcs determine loops. A secondary structure, represented by an arc diagram, is pseudoknot-free if its arc diagram does not present any crossing among arcs otherwise, it is said pseudoknotted. In this study, we face the problem of identifying a given structural pattern into secondary structures or the associated cores or shadow of both RNAs and RNA–RNA interactions, characterized by arbitrary pseudoknots. These abstractions are mapped into a matrix, whose elements represent the relations among loops. Therefore, we face the problem of taking advantage of matrices and submatrices. The algorithms, implemented in Python, work in polynomial time. We test our approach on a set of 16S ribosomal RNAs with inhibitors of Thermus thermophilus, and we quantify the structural effect of the inhibitors.

scholarly journals A Scan for Linkage Disequilibrium Across the Human Genome

Genetics ◽  
1999 ◽  
Vol 152 (4) ◽  
pp. 1711-1722 ◽  
Author(s):  
Gavin A Huttley ◽  
Michael W Smith ◽  
Mary Carrington ◽  
Stephen J O’Brien
Keyword(s):  
Linkage Disequilibrium ◽  
Human Genome ◽  
Pedigree Analysis ◽  
Exact Test ◽  
Genomic Scale ◽  
Genomic Regions ◽  
Formal Test ◽  
Scale Data ◽  
Short Tandem ◽  
Tandem Repeat Polymorphism

Abstract Linkage disequilibrium (LD), the tendency for alleles of linked loci to co-occur nonrandomly on chromosomal haplotypes, is an increasingly useful phenomenon for (1) revealing historic perturbation of populations including founder effects, admixture, or incomplete selective sweeps; (2) estimating elapsed time since such events based on time-dependent decay of LD; and (3) disease and phenotype mapping, particularly for traits not amenable to traditional pedigree analysis. Because few descriptions of LD for most regions of the human genome exist, we searched the human genome for the amount and extent of LD among 5048 autosomal short tandem repeat polymorphism (STRP) loci ascertained as specific haplotypes in the European CEPH mapping families. Evidence is presented indicating that ∼4% of STRP loci separated by <4.0 cM are in LD. The fraction of locus pairs within these intervals that display small Fisher’s exact test (FET) probabilities is directly proportional to the inverse of recombination distance between them (1/cM). The distribution of LD is nonuniform on a chromosomal scale and in a marker density-independent fashion, with chromosomes 2, 15, and 18 being significantly different from the genome average. Furthermore, a stepwise (locus-by-locus) 5-cM sliding-window analysis across 22 autosomes revealed nine genomic regions (2.2-6.4 cM), where the frequency of small FET probabilities among loci was greater than or equal to that presented by the HLA on chromosome 6, a region known to have extensive LD. Although the spatial heterogeneity of LD we detect in Europeans is consistent with the operation of natural selection, absence of a formal test for such genomic scale data prevents eliminating neutral processes as the evolutionary origin of the LD.

scholarly journals LncRNA:DNA triplex-forming sites are positioned at specific areas of genome organization and are predictors for Topologically Associated Domains

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Benjamin Soibam ◽  
Ayzhamal Zhamangaraeva
Keyword(s):  
Genome Organization ◽  
Chromatin Organization ◽  
Ctcf Binding ◽  
General Mechanism ◽  
Promoter Regions ◽  
Cellular Processes ◽  
A Genome ◽  
Topologically Associated Domains ◽  
Multiple Cell ◽  
Genomic Regions

Abstract Background Chromosomes are organized into units called topologically associated domains (TADs). TADs dictate regulatory landscapes and other DNA-dependent processes. Even though various factors that contribute to the specification of TADs have been proposed, the mechanism is not fully understood. Understanding the process for specification and maintenance of these units is essential in dissecting cellular processes and disease mechanisms. Results In this study, we report a genome-wide study that considers the idea of long noncoding RNAs (lncRNAs) mediating chromatin organization using lncRNA:DNA triplex-forming sites (TFSs). By analyzing the TFSs of expressed lncRNAs in multiple cell lines, we find that they are enriched in TADs, their boundaries, and loop anchors. However, they are evenly distributed across different regions of a TAD showing no preference for any specific portions within TADs. No relationship is observed between the locations of these TFSs and CTCF binding sites. However, TFSs are located not just in promoter regions but also in intronic, intergenic, and 3’UTR regions. We also show these triplex-forming sites can be used as predictors in machine learning models to discriminate TADs from other genomic regions. Finally, we compile a list of important “TAD-lncRNAs” which are top predictors for TADs identification. Conclusions Our observations advocate the idea that lncRNA:DNA TFSs are positioned at specific areas of the genome organization and are important predictors for TADs. LncRNA:DNA triplex formation most likely is a general mechanism of action exhibited by some lncRNAs, not just for direct gene regulation but also to mediate 3D chromatin organization.

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