Impact of Alu repeats on the evolution of human p53 binding sites

<p>Abstract</p> <p>Background</p> <p>The p53 tumor suppressor protein is involved in a complicated regulatory network, mediating expression of ~1000 human genes. Recent studies have shown that many p53 <it>in vivo </it>binding sites (BSs) reside in transposable repeats. The relationship between these BSs and functional p53 response elements (REs) remains unknown, however. We sought to understand whether the p53 REs also reside in transposable elements and particularly in the most-abundant Alu repeats.</p> <p>Results</p> <p>We have analyzed ~160 functional p53 REs identified so far and found that 24 of them occur in repeats. More than half of these repeat-associated REs reside in Alu elements. In addition, using a position weight matrix approach, we found ~400,000 potential p53 BSs in Alu elements genome-wide. Importantly, these putative BSs are located in the same regions of Alu repeats as the functional p53 REs - namely, in the vicinity of Boxes A/A' and B of the internal RNA polymerase III promoter. Earlier nucleosome-mapping experiments showed that the Boxes A/A' and B have a different chromatin environment, which is critical for the binding of p53 to DNA. Here, we compare the Alu-residing p53 sites with the corresponding Alu consensus sequences and conclude that the p53 sites likely evolved through two different mechanisms - the sites overlapping with the Boxes A/A' were generated by CG → TG mutations; the other sites apparently pre-existed in the progenitors of several Alu subfamilies, such as AluJo and AluSq. The binding affinity of p53 to the Alu-residing sites generally correlates with the age of Alu subfamilies, so that the strongest sites are embedded in the 'relatively young' Alu repeats.</p> <p>Conclusions</p> <p>The primate-specific Alu repeats play an important role in shaping the p53 regulatory network in the context of chromatin. One of the selective factors responsible for the frequent occurrence of Alu repeats in introns may be related to the p53-mediated regulation of Alu transcription, which, in turn, influences expression of the host genes.</p> <p>Reviewers</p> <p>This paper was reviewed by Igor B. Rogozin (nominated by Pavel A. Pevzner), Sandor Pongor, and I. King Jordan.</p

Hydration of a B-DNA Fragment in the Method of Atom-atom Correlation Functions with the Reference Interaction Site Model Approximation

We propose an efficient numerical algorithm for solving integral equations of the theory of liquids in the Reference Interaction Site Model (RISM) approximation for infinitely dilute solution of macromolecules with a large number of atoms. The algorithm is based on applying the nonstationary iterative methods for solving systems of linear algebraic equations. We calculate the solvent-solute atom-atom correlation functions for a fragment of the B-DNA duplex d(GGGGG).d(CCCCC) in infinitely dilute aqueous solution. The obtained results are compared with available experimental data and results from computer simulations.Comment: 9 pages, RevTeX, 9 pages of ps figures, accepted for publications in JC

Historical aspects of the problem of treatment of trigeminal neuralgia and the role of neurosurgical methods in its solution (literature review)

The trigeminal nerve is a mixed fifth cranial nerve, consisting of motor and sensory components. The sensitive component receives somesthetic information from the skin and mucous membranes of the face into the central nervous system, and the motor component is responsible for the innervation of chewing muscles. One of the manifestations of the pathology of the trigeminal nerve is pain syndrome. Trigeminal neuralgia occupies the main place among neurogenic pain syndrome in the face, is characterized by а severe course and the absence of sufficiently effective methods of treatment. According to the World Health Organization (WHO), the prevalence of trigeminal neuralgia in different countries is 2–5 cases per 100 thousand people per year. Trigeminal neuralgia is classified into 3 etiologic categories. Idiopathic trigeminal neuralgia occurs without apparent cause. Classical trigeminal neuralgia is caused by vascular compression of the trigeminal nerve root. Secondary trigeminal neuralgia is the consequence of a major neurologic disease, e. g., a tumor of the cеrеbеllоpоntine angle or multiple sclerosis. Today, there are many different options for the surgical treatment of trigeminal neuralgia. microvascular decompression of the root, radiosurgical destruction of the Gasser’s node, radiofrequency destruction, glycerol rhizotomy, balloon microcompression are considered the main effective and proven surgical methods for treating trigeminal neuralgia. But the questions of diagnosing the cause of the disease and choosing an adequate surgical method for treating therapeutically resistant trigeminal neuralgia for a particular patient remain open. The development of surgical methods begins from ancient times to the present day. The main stages in the development of neurosurgical treatment methods are presented. The following surgical techniques are described: open method – microvascular decompression, and closed percutaneous destructive methods – radiofrequency destruction, glycerol rhizotomy, balloon compression, radiosurgery, cryodestruction, laser destruction, botulinum toxin injections

Novel nucleosomal particles containing core histones and linker DNA but no histone H1

Eukaryotic chromosomal DNA is assembled into regularly spaced nucleosomes, which play a central role in gene regulation by determining accessibility of control regions. The nucleosome contains ∼147 bp of DNA wrapped ∼1.7 times around a central core histone octamer. The linker histone, H1, binds both to the nucleosome, sealing the DNA coils, and to the linker DNA between nucleosomes, directing chromatin folding. Micrococcal nuclease (MNase) digests the linker to yield the chromatosome, containing H1 and ∼160 bp, and then converts it to a core particle, containing ∼147 bp and no H1. Sequencing of nucleosomal DNA obtained after MNase digestion (MNase-seq) generates genome-wide nucleosome maps that are important for understanding gene regulation. We present an improved MNase-seq method involving simultaneous digestion with exonuclease III, which removes linker DNA. Remarkably, we discovered two novel intermediate particles containing 154 or 161 bp, corresponding to 7 bp protruding from one or both sides of the nucleosome core. These particles are detected in yeast lacking H1 and in H1-depleted mouse chromatin. They can be reconstituted in vitro using purified core histones and DNA. We propose that these \u27proto-chromatosomes\u27 are fundamental chromatin subunits, which include the H1 binding site and influence nucleosome spacing independently of H1

Long-range effects of histone point mutations on DNA remodeling revealed from computational analyses of SIN-mutant nucleosome structures

The packaging of DNA into nucleosomes impedes the binding and access of molecules involved in its processing. The SWI/SNF multi-protein assembly, found in yeast, is one of many regulatory factors that stimulate the remodeling of DNA required for its transcription. Amino-acid point mutations in histones H3 or H4 partially bypass the requirement of the SWI/SNF complex in this system. The mechanisms underlying the observed remodeling, however, are difficult to discern from the crystal structures of nucleosomes bearing these so-called SIN (SWI/SNF INdependent) mutations. Here, we report detailed analyses of the conformations and interactions of the histones and DNA in these assemblies. We find that the loss of direct protein–DNA contacts near point-mutation sites, reported previously, is coupled to unexpected additional long-range effects, i.e. loss of intermolecular contacts and accompanying DNA conformational changes at sequentially and spatially distant sites. The SIN mutations seemingly transmit information relevant to DNA binding across the nucleosome. The energetic cost of deforming the DNA to the states found in the SIN-mutant structures helps to distinguish the mutants that show phenotypes in yeast from those that do not. Models incorporating these deformed dimer steps suggest ways that nucleosomal DNA may be remodeled during its biological processing

ОПЫТ ПРИМЕНЕНИЯ НОВЫХ РЕЖИМОВ ЛЕЧЕНИЯ ТУБЕРКУЛЕЗА С МНОЖЕСТВЕННОЙ И ШИРОКОЙ ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТЬЮ ВОЗБУДИТЕЛЯ В РЕСПУБЛИКЕ БЕЛАРУСЬ

The objective of the study: to describe the efficiency and safety of new anti-tuberculosis drugs when treating tuberculosis patients with drug resistance.Subjects and methods. In Belarus, the retrospective and prospective analyses were performed in the cohort of 300 patients with multiple drug resistance and high rates of extensive drug resistance, who were treated with new drugs and drugs which were started to be used for the treatment of tuberculosis. In order to describe the cohort, blocks of variables were used to specify the efficiency and safety profiles of new anti-tuberculosis drugs.Results of the study. The high level of therapeutic efficiency of new regimens and their fairly favorable safety profile were demonstrated in the cohort.Цель исследования: характеристика профиля эффективности и безопасности использования новых противотуберкулезных лекарственных средств у пациентов с туберкулезом с лекарственной устойчивостью возбудителя.Материалы и методы. Проведен ретроспективный и проспективный анализ когорты из 300 пациентов с туберкулезом с множественной лекарственной устойчивостью возбудителя и высокой долей широкой лекарственной устойчивости, получавших новые и перепрофилированные противотуберкулезные лекарственные средства, в Республике Беларусь. Для описания когорты использовали группы переменных для характеристики профиля эффективности и профиля безопасности новых противотуберкулезных лекарственных средств.Результаты исследования. Продемонстрирован высокий уровень терапевтической эффективности в исследованной когорте, а также достаточно благоприятный профиль безопасности новых режимов

Interplay of Protein and DNA Structure Revealed in Simulations of the lac Operon

The E. coli Lac repressor is the classic textbook example of a protein that attaches to widely spaced sites along a genome and forces the intervening DNA into a loop. The short loops implicated in the regulation of the lac operon suggest the involvement of factors other than DNA and repressor in gene control. The molecular simulations presented here examine two likely structural contributions to the in-vivo looping of bacterial DNA: the distortions of the double helix introduced upon association of the highly abundant, nonspecific nucleoid protein HU and the large-scale deformations of the repressor detected in low-resolution experiments. The computations take account of the three-dimensional arrangements of nucleotides and amino acids found in crystal structures of DNA with the two proteins, the natural rest state and deformational properties of protein-free DNA, and the constraints on looping imposed by the conformation of the repressor and the orientation of bound DNA. The predicted looping propensities capture the complex, chain-length-dependent variation in repression efficacy extracted from gene expression studies and in vitro experiments and reveal unexpected chain-length-dependent variations in the uptake of HU, the deformation of repressor, and the folding of DNA. Both the opening of repressor and the presence of HU, at levels approximating those found in vivo, enhance the probability of loop formation. HU affects the global organization of the repressor and the opening of repressor influences the levels of HU binding to DNA. The length of the loop determines whether the DNA adopts antiparallel or parallel orientations on the repressor, whether the repressor is opened or closed, and how many HU molecules bind to the loop. The collective behavior of proteins and DNA is greater than the sum of the parts and hints of ways in which multiple proteins may coordinate the packaging and processing of genetic information. © 2013 Czapla et al