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Non canonical DNA

Peter V Deraska, Colin O'Leary, Hunter D Reavis, Shelby Labe, Tru-Khang Dinh, Jean-Bernard Lazaro, Christopher Sweeney, Alan D D'Andrea, David Kozono
Despite optimal chemotherapy, radiotherapy (RT), and/or surgery, non-small-cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the US and worldwide. Thoracic RT, a mainstay in the treatment of locally advanced NSCLC, is often restricted in efficacy by a therapeutic index limited by sensitivity of tissues surrounding the malignancy. Therefore, radiosensitizers that can improve the therapeutic index are a vital unmet need. Inhibition of the NF-κB pathway is a proposed mechanism of radiosensitization...
December 2018: Cell Death Discovery
Xiaoxian Wu, Diane L Haakonsen, Allen G Sanderlin, Yue J Liu, Liqiang Shen, Ningning Zhuang, Michael T Laub, Yu Zhang
Canonical bacterial transcription activators bind to non-transcribed promoter elements to increase transcription of their target genes. Here we report crystal structures of binary complexes comprising domains of Caulobacter crescentus GcrA, a noncanonical bacterial transcription factor, that support a novel mechanism for transcription activation through the preferential binding of methylated cis-regulatory elements and the promotion of open complex formation through an interaction with region 2 of the principal σ factor, σ70...
March 5, 2018: Nucleic Acids Research
Micol Falabella, Rafael J Fernandez, Brad Johnson, Brett A Kaufman
Some DNA or RNA sequences rich in guanine (G) nucleotides can adopt non-canonical conformations known as G-quadruplexes (G4). In the nuclear genome, G4 motifs have been associated with genome instability and gene expression defects, but they are increasingly recognized to be regulatory structures. Recent studies have revealed that G4 structures can form in the mitochondrial genome (mtDNA) and G4 forming potential sequences are associated with the origin of mtDNA deletions. However, little is known about the regulatory role of G4 structures in mitochondria...
February 28, 2018: Current Medicinal Chemistry
Bee Gek Ng, Jae Woo Han, Dong Wan Lee, Gyung Ja Choi, Beom Seok Kim
Hahella chejuensis MB-1084 is a Gram-negative marine bacterial strain that produces unusual 17-membered carbocyclic tetraenes, chejuenolide A and B. Two fosmid clones responsible for chejuenolide production were identified from the genomic DNA library of the MB-1084 strain. Systematic inactivation of the open reading frames (ORFs) in the sequenced region defines the boundaries of the chejuenolide (che) biosynthetic gene cluster (24.9 kbp) that encodes one non-ribosomal peptide synthase (NRPS)-polyketide synthase (PKS) hybrid protein, three modular PKSs, two PKS domains, and an amine oxidase homolog...
February 26, 2018: Journal of Antibiotics
Vladimir B Tsvetkov, Timofei S Zatsepin, Evgeny S Belyaev, Yury I Kostyukevich, George V Shpakovski, Victor V Podgorsky, Galina E Pozmogova, Anna M Varizhuk, Andrey V Aralov
Non-canonical DNA structures are widely used for regulation of gene expression, in DNA nanotechnology and for the development of new DNA-based sensors. I-motifs (iMs) are two intercalated parallel duplexes that are held together by hemiprotonated C-C base pairs. Previously, iMs were used as an accurate sensor for intracellular pH measurements. However, iM stability is moderate, which in turn limits its in vivo applications. Here, we report the rational design of a new substituted phenoxazine 2'-deoxynucleotide (i-clamp) for iM stabilization...
February 21, 2018: Nucleic Acids Research
Yossi Saragani, Amnon Hizi, Galia Rahav, Sara Zaouch, Mary Bakhanashvili
HIV-1 reverse transcriptase (RT) in the cytoplasm of HIV-infected cells efficiently inserts the non-canonical dUTP into the proviral DNA, and extends the dU-terminated DNA. The misincorporation of dUTP leads to mutagenesis, and uracils can down-regulate viral gene expression. However, uracilation might also protect HIV DNA from auto-integration in the cytoplasm. Tumor suppressor p53 protein, exhibiting inherent 3'→5' exonuclease activity, provides a potential host-derived repair mechanism during HIV reverse transcription for the misincorporation of various wrong nucleotides, leading to both base-base mismatches and incorporated non-canonical ribonucleotides...
February 19, 2018: Biochemical and Biophysical Research Communications
Laura J Eccles, Andrew C Bell, Simon N Powell
When Fanconi Anemia (FA) proteins were depleted in human U2OS cells with integrated DNA repair reporters, we observed decreases in homologous recombination (HR), decreases in mutagenic non-homologous end joining (m-NHEJ) and increases in canonical NHEJ, which was independently confirmed by measuring V(D)J recombination. Furthermore, depletion of FA proteins resulted in reduced HR protein foci and increased NHEJ protein recruitment to replication-associated DSBs, consistent with our observation that the use of canonical NHEJ increases after depletion of FA proteins in cycling cells...
February 10, 2018: DNA Repair
Felipe Cava
In this monographic issue, we have the pleasure to present contributions from six of the leading laboratories at the forefront of Vibrio cholerae genetics, ecology and evolution, together with a brief tribute by Diego Romero to Doctor Jaime Ferrán y Clua, a pioneering Spanish bacteriologist who developed the first vaccine against this pathogen. V. cholerae is a free-living aquatic bacterium that interacts with and infects a variety of organisms. In humans it causes cholera, the deadly diarrhoea that was responsible for millions of deaths during seven pandemics since 1817, and still thousands every year...
September 2017: International Microbiology: the Official Journal of the Spanish Society for Microbiology
Daniel A Truchado, Michaël A J Moens, Sergio Callejas, Javier Pérez-Tris, Laura Benítez
Papillomaviruses are non-enveloped, DNA viruses that infect skin and mucosa of a wide variety of vertebrates, causing neoplasias or simply persisting asymptomatically. Avian papillomaviruses, with six fully sequenced genomes, are the second most studied group after mammalian papillomaviruses. In this study, we describe the first oral avian papillomavirus, detected in the tongue of a dead Yorkshire canary (Serinus canaria) and in oral swabs of the same bird and other two live canaries from an aviary in Madrid, Spain...
February 14, 2018: Veterinary Research Communications
Yabin Guo, Yin Zhang, Kaishun Hu
Background: Sleeping Beauty transposon (SB) has become an increasingly important genetic tool for generating mutations in vertebrate cells. It is widely thought that SB exclusively integrates into TA dinucleotides. However, this strict TA-preference has not been rigorously tested in large numbers of insertion sites that now can be detected with next generation sequencing. Li et al. found 71 SB insertions in non-TA dinucleotides in 2013, suggesting that TA dinucleotides are not the only sites of SB integration, yet further studies on this topic have not been carried out...
2018: Mobile DNA
Stanislav S Bachurin, Mikhail E Kletskii, Oleg N Burov, Sergey V Kurbatov
A study of relative thermodynamic stability of non-canonical DNA structures (triplexes, G-quadruplexes, i-motifs) for the first time was conducted on the basis of quantum chemical DFT/B3LYP/6-31++G (d) calculations. Results of the calculations completely reproduce the experimental data on stability of G-quadruplexes comparatively Watson-Crick B-DNA. It was discovered that combinations of non-canonical DNA structures were energetically more favorable than separated nitrogenous bases. Supramolecular complexes of the non-canonical DNA structures (NSs) can be considered as a biological drug targets in gene regulation (for example in tumor therapy), in contrast to previous works, where NSs were studied independently...
February 8, 2018: Biophysical Chemistry
Ming Zhao, Yixin Tan, Qiao Peng, Cancan Huang, Yu Guo, Gongping Liang, Bochen Zhu, Yi Huang, Aiyun Liu, Zijun Wang, Mengying Li, Xiaofei Gao, Ruifang Wu, Haijing Wu, Hai Long, Qianjin Lu
Epigenetic modifications affect the differentiation of T cell subsets and the pathogenesis of autoimmune diseases, but many mechanisms of epigenetic regulation of T cell differentiation are unclear. Here we show reduced expression of the transcription factor RFX1 in CD4+ T cells from patients with systemic lupus erythematosus, which leads to IL-17A overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 tri-methylation. Conditional deletion of Rfx1 in mice exacerbates experimental autoimmune encephalomyelitis and pristane-induced lupus-like syndrome and increases induction of Th17 cells...
February 8, 2018: Nature Communications
Shelly Sorrells, Sara Nik, Mattie Casey, Rosannah C Cameron, Harold Truong, Cristhian Toruno, Michelle Gulfo, Albert Lowe, Cicely Jette, Rodney A Stewart, Teresa V Bowman
RNA splicing factors are essential for the viability of all eukaryotic cells; however, in metazoans some cell types are exquisitely sensitive to disruption of splicing factors, such as neuronal cells which can lead to neurodegenerative diseases. The basis for this tissue selectivity is not well understood due to difficulties in analyzing the consequences of splicing factor defects in whole animal systems. Here, we use zebrafish mutants to show that loss of spliceosomal components, including splicing factor 3b, subunit 1 (sf3b1), caused increased DNA double-strand breaks and apoptosis in embryonic neurons with a concomitant accumulation of R-loops, which are non-canonical nucleic acid structures that promote genomic instability...
January 29, 2018: Disease Models & Mechanisms
Jamie R Johnston, P Bryant Chase, Jose Renato Pinto
Troponin is a heterotrimeric Ca2+-binding protein that has a well-established role in regulating striated muscle contraction. However, mounting evidence points to novel cellular functions of troponin, with profound implications in cancer, cardiomyopathy pathogenesis and skeletal muscle aging. Here, we highlight the non-canonical roles and aberrant expression patterns of troponin beyond the sarcomeric milieu. Utilizing bioinformatics tools and online databases, we also provide pathway, subcellular localization, and protein-protein/DNA interaction analyses that support a role for troponin in multiple subcellular compartments...
January 2, 2018: Oncotarget
Nathan Beals, Michael Model, Matt Worden, Torsten Hegmann, Soumitra Basu
Over the past decade, nanomedicine has gained considerable traction through its relevance, for example in "smart" delivery, thus creating platforms for novel treatments. Here we report a natural polymer-DNA conjugate that undergoes self-assembly in a K+ dependent fashion to form a G-quadruplex (GQ) and generate superpolymeric structures. We derivatized the naturally occurring glycosaminoglycan polymer hyaluronic acid (HA) with short G-rich DNA (HASH-DNA) that can form intermolecular non-canonical GQ structure...
February 5, 2018: ACS Applied Materials & Interfaces
Grover Bagby
Fanconi anemia is an inherited disease characterized by genomic instability, hypersensitivity to DNA cross-linking agents, bone marrow failure, short stature, skeletal abnormalities, and a high relative risk of myeloid leukemia and epithelial malignancies. The 21 Fanconi anemia genes encode proteins involved in multiple nuclear biochemical pathways that effect DNA interstrand crosslink repair. In the past, bone marrow failure was attributed solely to the failure of stem cells to repair DNA. Recently, non-canonical functions of many of the Fanconi anemia proteins have been described, including modulating responses to oxidative stress, viral infection, and inflammation as well as facilitating mitophagic responses and enhancing signals that promote stem cell function and survival...
2018: F1000Research
Bastian Stielow, Florian Finkernagel, Thorsten Stiewe, Andrea Nist, Guntram Suske
Diverse Polycomb repressive complexes 1 (PRC1) play essential roles in gene regulation, differentiation and development. Six major groups of PRC1 complexes that differ in their subunit composition have been identified in mammals. How the different PRC1 complexes are recruited to specific genomic sites is poorly understood. The Polycomb Ring finger protein PCGF6, the transcription factors MGA and E2F6, and the histone-binding protein L3MBTL2 are specific components of the non-canonical PRC1.6 complex. In this study, we have investigated their role in genomic targeting of PRC1...
January 30, 2018: PLoS Genetics
Jeff Nivala, Seth L Shipman, George M Church
The adaptation phase of CRISPR-Cas immunity depends on the precise integration of short segments of foreign DNA (spacers) into a specific genomic location within the CRISPR locus by the Cas1-Cas2 integration complex. Although off-target spacer integration outside of canonical CRISPR arrays has been described in vitro, no evidence of non-specific integration activity has been found in vivo. Here, we show that non-canonical off-target integrations can occur within bacterial chromosomes at locations that resemble the native CRISPR locus by characterizing hundreds of off-target integration locations within Escherichia coli...
January 29, 2018: Nature Microbiology
Lutan Liu, Byul G Kim, Ujala Feroze, Robert B Macgregor, Tigran V Chalikian
G-quadruplexes and i-motifs are non-canonical secondary structures of DNA that appear to play a number of regulatory roles in the genome with clear connection to disease. Characterization of the forces stabilizing these structures is necessary for developing an ability to induce of G-quadruplex and/or i-motif structures at selected genomic loci in a controlled manner. We report here the results of pH-dependent acoustic and densimetric measurements and UV melting experiments at high pressures to scrutinize changes in hydration and ionic atmosphere accompanying i-motif formation by the C-rich DNA sequence from the promoter region of the human c-MYC oncogene [5'-d(TTA¬CCC¬ACCCTACCCACCCTCA)] (ODN)...
January 22, 2018: Journal of the American Chemical Society
Tito Candelli, Drice Challal, Jean-Baptiste Briand, Jocelyne Boulay, Odil Porrua, Jessie Colin, Domenico Libri
Transcription termination delimits transcription units but also plays important roles in limiting pervasive transcription. We have previously shown that transcription termination occurs when elongating RNA polymerase II (RNAPII) collides with the DNA-bound general transcription factor Reb1. We demonstrate here that many different DNA-binding proteins can induce termination by a similar roadblock (RB) mechanism. We generated high-resolution transcription maps by the direct detection of RNAPII upon nuclear depletion of two essential RB factors or when the canonical termination pathways for coding and non-coding RNAs are defective...
January 19, 2018: EMBO Journal
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