scholarly journals An extended APOBEC3A mutation signature in cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Adam Langenbucher ◽  
Danae Bowen ◽  
Ramin Sakhtemani ◽  
Elodie Bournique ◽  
Jillian F. Wise ◽  
...  
Keyword(s):  
Secondary Structure ◽  
The Other ◽  
Twin Paradox ◽  
Cancer Evolution ◽  
Dna Hairpin ◽  
Sequence Preference ◽  
Mutational Hotspots ◽  
Hairpin Loops ◽  
Cancer Genomes ◽  
Driver Event

AbstractAPOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA. Recently, we showed that APOBEC3A (A3A) targets DNA hairpin loops. Here, we show that DNA secondary structure is in fact an orthogonal influence on A3A substrate optimality and, surprisingly, can override the TpC sequence preference. VpC (non-TpC) sites in optimal hairpins can outperform TpC sites as mutational hotspots. This expanded understanding of APOBEC mutagenesis illuminates the genomic Twin Paradox, a puzzling pattern of closely spaced mutation hotspots in cancer genomes, in which one is a canonical TpC site but the other is a VpC site, and double mutants are seen only in trans, suggesting a two-hit driver event. Our results clarify this paradox, revealing that both hotspots in these twins are optimal A3A substrates. Our findings reshape the notion of a mutation signature, highlighting the additive roles played by DNA sequence and DNA structure.

RNAknot: A new algorithm for RNA secondary structure prediction based on genetic algorithm and GRASP method

2019 ◽  
Vol 17 (05) ◽  
pp. 1950031 ◽  
Author(s):  
Abdelhakim El Fatmi ◽  
M. Ali Bekri ◽  
Said Benhlima
Keyword(s):  
Genetic Algorithm ◽  
Secondary Structure ◽  
Structure Prediction ◽  
Rna Secondary Structure ◽  
Secondary Structure Prediction ◽  
Fitness Function ◽  
The Other ◽  
Rna Sequences ◽  
Rna Secondary Structure Prediction ◽  
Hairpin Loops

The prediction of the optimal secondary structure for a given RNA sequence represents a challenging computational problem in bioinformatics. This challenge becomes harder especially with the discovery of different pseudoknot classes, which is a complex topology that plays diverse roles in biological processes. Many recent studies have been proposed to predict RNA secondary structure with some pseudoknot classes, but only a few of them have reached satisfying results in terms of both complexity and accuracy. Here we present RNAknot, a new method for predicting RNA secondary structure that contains the following components: stems, hairpin loops, multi-branched loops or multi-loops, bulge loops, and internal loops, in addition to two types of pseudoknots, H-type pseudoknot and Hairpin kissing. RNAknot is based on a genetic algorithm and Greedy Randomized Adaptive Search Procedure (GRASP), and it uses the free energy as fitness function to evaluate the obtained structures. In order to validate the performance of the presented method 131 tests have been performed using two datasets of 26 and 105 RNA sequences, which have been taken from the two data bases RNAstrand and Pseudobase respectively. The obtained results are compared with those of some RNA secondary structure prediction programs such as Vs_subopt, CyloFold, IPknot, Kinefold, RNAstructure, and Sfold. The results of this comparative study show that the prediction accuracy of our proposed approach is significantly improved compared to those obtained by the other programs. For the first dataset, RNAknot has the highest specificity (SP) (71.23%) and sensitivity (SN) (72.15%) averages compared to the other programs. Concerning the second dataset, the RNA secondary structure predictions obtained by the RNAknot correspond to the highest averages of SP (85.49%) and F-measure (79.97%) compared to the other programs. The program is available as a jar file in the link: www.bachmek.umi.ac.ma/wp-content/uploads/RNAknot.0.0.2.rar .

scholarly journals A study of the alkaline hydrolysis of fractionated reticulocyte ribosomal ribonucleic acid and its relevance to secondary structure

1968 ◽  
Vol 106 (3) ◽  
pp. 733-741 ◽  
Author(s):  
R A Cox ◽  
Hannah J. Gould ◽  
K Kanagalingam
Keyword(s):  
Secondary Structure ◽  
Phosphate Buffer ◽  
Potassium Hydroxide ◽  
Chain Scission ◽  
Average Chain Length ◽  
Guanidinium Chloride ◽  
Stable Species ◽  
Hairpin Loops ◽  
Ribosomal Ribonucleic Acid ◽  
Hydrolysis Of

1. RNA isolated from the sub-units of rabbit reticulocyte ribosomes was hydrolysed by 0·4n-potassium hydroxide at 20°. The probability of main-chain scission was calculated from the number-average chain length, which was obtained from S25,w in 0·01m-phosphate buffer. 2. The fraction, f, of the original secondary structure that the fragments re-formed at neutral pH in 4m-guanidinium chloride, as well as in 0·01m- and 0·1m-phosphate buffer, was derived from changes in extinction over the range 220–310mμ on thermal denaturation. 3. The secondary structure of RNA is regarded as an assembly of hairpin loops each of 2N+b residues on average, where N is the number of base-paired residues and b is the number of unpaired residues. 4. If chain scission takes place at random then 2N+b=logf/log(1–p). 5. For RNA from the smaller sub-unit 2N+b was estimated as 25±5 residues, compared with 30±5 residues for the less stable species and 35±5 residues for the more stable species of hairpin loop of RNA from the larger sub-unit.

scholarly journals The “twin paradox”: the role of acceleration

2019 ◽  
Vol 97 (10) ◽  
pp. 1049-1063
Author(s):  
J. Gamboa ◽  
F. Mendez ◽  
M.B. Paranjape ◽  
Benoit Sirois
Keyword(s):  
Reference Frame ◽  
Relative Motion ◽  
Complete Resolution ◽  
Proper Time ◽  
The Other ◽  
Twin Paradox ◽  
Age Difference ◽  
Inertial Reference Frame

The “twin paradox” corresponds to the situation where two twins begin at rest in an inertial reference frame, one of them takes a journey, normally very fast and to a distant place, and then returns to the twin at rest. The “twin paradox” evokes the idea that each twin would say that it should be the other who is younger because of their relative motion. A complete resolution of the paradox corresponds to the calculation of the elapsed proper time of each twin, by each twin, and the subsequent observation that they actually get the same answer, that the travelling twin is indeedthe younger twin. Acceleration has a role to play; indeed, if one tries to calculate the age difference from the point of the view of the travelling twin, then the role of the acceleration is crucial and cannot be dismissed. In this tutorial, we show in complete and pedagogical detail, how to do the necessary calculations according to each twin using simple transformations of coordinates.

Asymmetric structure of five and six membered DNA hairpin loops

1996 ◽  
Vol 22 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Ulrich Baumann ◽  
Sherwood Chang
Keyword(s):  
Asymmetric Structure ◽  
Dna Hairpin ◽  
Hairpin Loops

scholarly journals Quantitative Binding of Divalent Metal Ions to DNA Hairpin Loops

2019 ◽  
Vol 116 (3) ◽  
pp. 285a
Author(s):  
Harrison Russell ◽  
William Gunderson ◽  
Julie Gunderson
Keyword(s):  
Metal Ions ◽  
Divalent Metal ◽  
Divalent Metal Ions ◽  
Dna Hairpin ◽  
Hairpin Loops

scholarly journals The Role of DNA-PKcs and Artemis in Opening Viral DNA Hairpin Termini in Various Tissues in Mice

2007 ◽  
Vol 81 (20) ◽  
pp. 11304-11321 ◽  
Author(s):  
Katsuya Inagaki ◽  
Congrong Ma ◽  
Theresa A. Storm ◽  
Mark A. Kay ◽  
Hiroyuki Nakai
Keyword(s):  
Dna Repair ◽  
Inverted Terminal Repeat ◽  
Dependent Manner ◽  
Dna Hairpin ◽  
Dna Hairpins ◽  
Alternative Pathways ◽  
Hairpin Loops ◽  
Dependent Protein ◽  
Significant Pathway ◽  
Cellular Dna

ABSTRACT A subset of cellular DNA hairpins at double-strand breaks is processed by DNA-dependent protein kinase catalytic subunit (DNA-PKcs)- and Artemis-associated endonuclease. DNA hairpin termini of adeno-associated virus (AAV) are processed by DNA repair machinery; however, how and what cellular factors are involved in the process remain elusive. Here, we show that DNA-PKcs and Artemis open AAV inverted terminal repeat (ITR) hairpin loops in a tissue-dependent manner. We investigated recombinant AAV (rAAV) genome metabolism in various tissues of DNA-PKcs- or Artemis-proficient or -deficient mice. In the absence of either factor, ITR hairpin opening was impaired, resulting in accumulation of double-stranded linear rAAV genomes capped with covalently closed hairpins at termini. The 5′ end of 3-base hairpin loops of the ITR was the primary target for DNA-PKcs- and Artemis-mediated cleavage. In the muscle, heart, and kidney, DNA-PKcs- and Artemis-dependent hairpin opening constituted a significant pathway, while in the liver, undefined alternative pathways effectively processed hairpins. In addition, our study revealed a Holliday junction resolvase-like activity in the liver that cleaved T-shaped ITR hairpin shoulders by making nicks at diametrically opposed sites. Thus, our approach furthers our understanding of not only rAAV biology but also fundamental DNA repair systems in various tissues of living animals.

The topological trapping of circular DNAs on agarose: Unexpected restrictions on DNA rotation

1978 ◽  
Vol 56 (6) ◽  
pp. 585-591 ◽  
Author(s):  
Jeremy S. Lee ◽  
A. Richard Morgan
Keyword(s):  
Secondary Structure ◽  
Binding Constant ◽  
Binding Assay ◽  
Sodium Perchlorate ◽  
Binding Constants ◽  
The Other ◽  
Calf Thymus ◽  
Potential Applications ◽  
Open Circular ◽  
Circular Dnas

DNA linked to an insoluble matrix has many potential applications. In some cases, it is highly desirable that the DNA be chemically unaltered, and for this reason, we have developed methods for topologically trapping circular DNAs on agarose. Open circular (oc) DNA containing at least one nick is readily trapped on agarose which has been heated or dissolved in sodium perchlorate to destroy secondary structure and then gelled by cooling or dialysis respectively. On the other hand, covalently closed circular (ccc) DNA of superhelix density −0.12 (PM2 DNA) is only poorly trapped unless first relaxed by topoisomerases or with the appropriate addition of an intercalating drug. When the oc DNA – agarose was used in a procedure for rapidly obtaining binding constants of drugs to DNA, the binding constant of ethidium was found to be considerably less than that expected. On addition of calf thymus topoisomerase to the binding-assay mixture, the ethidium-binding constant increased to the expected value. Thus, although free oc DNA is topologically unrestricted, oc DNA trapped in agarose must be rotationally constrained such that addition of ethidium introduced supercoils. The nature of these constraints is discussed with respect to the known structure of agarose bihelices.

scholarly journals Structural and Functional Changes of Reconstituted High-Density Lipoprotein (HDL) by Incorporation of α-synuclein: A Potent Antioxidant and Anti-Glycation Activity of α-synuclein and apoA-I in HDL at High Molar Ratio of α-synuclein

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7485
Author(s):  
Kyung-Hyun Cho
Keyword(s):  
Amino Acids ◽  
Secondary Structure ◽  
Expression System ◽  
Lipoprotein Metabolism ◽  
The Other ◽  
Ldl Oxidation ◽  
Molar Ratio ◽  
Binding Ability ◽  
Functional Changes ◽  
Other Hand

α-synuclein (α-syn) is a major culprit of Parkinson’s disease (PD), although lipoprotein metabolism is very important in the pathogenesis of PD. α-syn was expressed and purified using the pET30a expression vector from an E. coli expression system to elucidate the physiological effects of α-syn on lipoprotein metabolism. The human α-syn protein (140 amino acids) with His-tag (8 amino acids) was expressed and purified to at least 95% purity. Isoelectric focusing gel electrophoresis showed that the isoelectric point (pI) of α-syn and apoA-I were pI = 4.5 and pI = 6.4, respectively. The lipid-free α-syn showed almost no phospholipid-binding ability, while apoA-I showed rapid binding ability with a half-time (T1/2) = 8 ± 0.7 min. The α-syn and apoA-I could be incorporated into the reconstituted HDL (rHDL, molar ratio 95:5:1:1, palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I:α-syn with the production of larger particles (92 Å) than apoA-I-rHDL (86 and 78 Å) and α-syn-rHDL (65 Å). An rHDL containing both apoA-I and α-syn showed lower α-helicity around 45% with a red shift of the Trp wavelength maximum fluorescence (WMF) from 339 nm, while apoA-I-HDL showed 76% α-helicity and 337 nm of WMF. The denaturation by urea addition showed that the incorporation of α-syn in rHDL caused a larger increase in the WMF than apoA-I-rHDL, suggesting that the destabilization of the secondary structure of apoA-I by the addition of α-syn. On the other hand, the addition of α-syn induced two-times higher resistance to rHDL glycation at apoA-I:α-syn molar ratios of 1:1 and 1:2. Interestingly, low α-syn in rHDL concentrations, molar ratio of 1:0.5 (apoA-I:α-syn), did not prevent glycation with more multimerization of apoA-I. In the lipid-free and lipid-bound state, α-syn showed more potent antioxidant activity than apoA-I against cupric ion-mediated LDL oxidation. On the other hand, microinjection of α-syn (final 2 μM) resulted in 10% less survival of zebrafish embryos than apoA-I. A subcutaneous injection of α-syn (final 34 μM) resulted in less tail fin regeneration than apoA-I. Interestingly, incorporation of α-syn at a low molar ratio (apoA-I:α-syn, 1:0.5) in rHDL resulted destabilization of the secondary structure and impairment of apoA-I functionality via more oxidation and glycation. However, at a higher molar ratio of α-syn in rHDL (apoA-I:α-syn = 1:1 or 1:2) exhibited potent antioxidant and anti-glycation activity without aggregation. In conclusion, there might be a critical concentration of α-syn and apoA-I in HDL-like complex to prevent the aggregation of apoA-I via structural and functional enhancement.

scholarly journals Identifying Simultaneous Rearrangements in Cancer Genomes

2017 ◽  
Author(s):  
Layla Oesper ◽  
Simone Dantas ◽  
Benjamin J. Raphael
Keyword(s):  
Simulated Data ◽  
Cancer Genome ◽  
Derivative Chromosome ◽  
Cancer Evolution ◽  
Catastrophic Event ◽  
Cancer Dataset ◽  
Long Period ◽  
Useful Signal ◽  
Cancer Genomes ◽  
Precise Quantification

AbstractThe traditional view of cancer evolution states that a cancer genome accumulates a sequential ordering of mutations over a long period of time. However, in recent years it has been suggested that a cancer genome may instead undergo a one-time catastrophic event, such as chromothripsis, where a large number of mutations instead occur simultaneously. A number of potential signatures of chromothripsis have been proposed. In this work we provide a rigorous formulation and analysis of the “ability to walk the derivative chromosome” signature originally proposed by Korbel and Campbell (2013). In particular, we show that this signature, as originally envisioned, may not always be present in a chromothripsis genome and we provide a precise quantification of under what circumstances it would be present. We also propose a variation on this signature, the H/T alternating fraction, which allows us to overcome some of the limitations of the original signature. We apply our measure to both simulated data and a previously analyzed real cancer dataset and find that the H/T alternating fraction may provide useful signal for distinguishing genomes having acquired mutations simultaneously from those acquired in a sequential fashion. An implementation of the H/T alternating fraction is available at https://bitbucket.org/oesperlab/ht-altfrac.

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