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"R-loops"

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https://www.readbyqxmd.com/read/28717002/human-ribonuclease-h1-resolves-r-loops-and-thereby-enables-progression-of-the-dna-replication-fork
#1
Shankar Parajuli, Daniel C Tealsey, Bhavna Murali, Jessica Jackson, Alessandro Vindigni, Sheila A Stewart
Faithful DNA replication is essential for genome stability. To ensure accurate replication, numerous complex and redundant replication and repair mechanisms function in tandem with the core replication proteins to ensure DNA replication continues even when replication challenges are present that could impede progression of the replication fork. A unique topological challenge to the replication machinery is posed by RNA:DNA hybrids, commonly referred to as R-loops. While R-loops play important roles in gene expression and recombination at immunoglobulin sites, their persistence is thought to interfere with DNA replication by slowing or impeding replication fork progression...
July 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28714954/c9orf72-expansion-disrupts-atm-mediated-chromosomal-break-repair
#2
Callum Walker, Saul Herranz-Martin, Evangelia Karyka, Chunyan Liao, Katherine Lewis, Waheba Elsayed, Vera Lukashchuk, Shih-Chieh Chiang, Swagat Ray, Padraig J Mulcahy, Mateusz Jurga, Ioannis Tsagakis, Tommaso Iannitti, Jayanth Chandran, Ian Coldicott, Kurt J De Vos, Mohamed K Hassan, Adrian Higginbottom, Pamela J Shaw, Guillaume M Hautbergue, Mimoun Azzouz, Sherif F El-Khamisy
Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks...
July 17, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28696814/ddx19-links-mrna-nuclear-export-with-progression-of-transcription-and-replication-and-suppresses-genomic-instability-upon-dna-damage-in-proliferating-cells
#3
Dana Hodroj, Kamar Serhal, Domenico Maiorano
The DEAD-box Helicase 19 (Ddx19) gene codes for an RNA helicase involved in both messenger RNA (mRNA) export from the nucleus into the cytoplasm and in mRNA translation. In unperturbed cells, Ddx19 localizes in the cytoplasm and at the cytoplasmic face of the nuclear pore. Here we review recent findings related to an additional Ddx19 function in the nucleus in resolving RNA:DNA hybrids (R-loops) generated during collision between transcription and replication, and upon DNA damage. Activation of a DNA damage response pathway dependent upon the ATR kinase, a major regulator of replication fork progression, stimulates translocation of the Ddx19 protein from the cytoplasm into the nucleus...
July 11, 2017: Nucleus
https://www.readbyqxmd.com/read/28678773/erratum-structure-of-the-cpf1-endonuclease-r-loop-complex-after-target-dna-cleavage
#4
Stefano Stella, Pablo Alcón, Guillermo Montoya
This corrects the article DOI: 10.1038/nature22398.
July 5, 2017: Nature
https://www.readbyqxmd.com/read/28673893/from-intronization-to-intron-loss-how-the-interplay-between-mrna-associated-processes-can-shape-the-architecture-and-the-expression-of-eukaryotic-genes
#5
Francesco Catania
Transcription-coupled processes such as capping, splicing, and cleavage/polyadenylation participate in the journey from genes to proteins. Although they are traditionally thought to serve only as steps in the generation of mature mRNAs, a synthesis of available data indicates that these processes could also act as a driving force for the evolution of eukaryotic genes. A theoretical framework for how mRNA-associated processes may shape gene structure and expression has recently been proposed. Factors that promote splicing and cleavage/polyadenylation in this framework compete for access to overlapping or neighboring signals throughout the transcription cycle...
June 30, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28666126/telomere-length-determines-terra-and-r-loop-regulation-through-the-cell-cycle
#6
Marco Graf, Diego Bonetti, Arianna Lockhart, Kamar Serhal, Vanessa Kellner, André Maicher, Pascale Jolivet, Maria Teresa Teixeira, Brian Luke
Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28666122/structure-basis-for-directional-r-loop-formation-and-substrate-handover-mechanisms-in-type-i-crispr-cas-system
#7
Yibei Xiao, Min Luo, Robert P Hayes, Jonathan Kim, Sherwin Ng, Fang Ding, Maofu Liao, Ailong Ke
Type I CRISPR systems feature a sequential dsDNA target searching and degradation process, by crRNA-displaying Cascade and nuclease-helicase fusion enzyme Cas3, respectively. Here we present two cryo-EM snapshots of the Thermobifida fusca type I-E Cascade: (1) unwinding 11 bp of dsDNA at the seed-sequence region to scout for sequence complementarity, and (2) further unwinding of the entire protospacer to form a full R-loop. These structures provide the much-needed temporal and spatial resolution to resolve key mechanistic steps leading to Cas3 recruitment...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28658920/management-of-an-unusual-ectopic-eruption-of-maxillary-canine
#8
Kaladhar Reddy Aileni, Madhukar Reddy Rachala, Chintakunta Reddy Prathima, Pitalla Kumar Naveen, Donthula Soujanya
Transposition of teeth is a rare condition, with a prevalence of 0.3-0.4% in general population. They are more commonly observed in females, and may occur unilaterally/bilaterally with greater frequency of left side occurrence in unilateral transposition cases. A 17-year-old female patient reported with the chief complaint of unaesthetic smile. On clinical examination the patient was diagnosed with Angle's class I malocclusion with an ectopically erupted maxillary left canine labial to the left central incisor with retained deciduous canine...
May 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28653981/the-role-of-replication-associated-repair-factors-on-r-loops
#9
REVIEW
Vaibhav Bhatia, Emilia Herrera-Moyano, Andrés Aguilera, Belén Gómez-González
The nascent RNA can reinvade the DNA double helix to form a structure termed the R-loop, where a single-stranded DNA (ssDNA) is accompanied by a DNA-RNA hybrid. Unresolved R-loops can impede transcription and replication processes and lead to genomic instability by a mechanism still not fully understood. In this sense, a connection between R-loops and certain chromatin markers has been reported that might play a key role in R-loop homeostasis and genome instability. To counteract the potential harmful effect of R-loops, different conserved messenger ribonucleoprotein (mRNP) biogenesis and nuclear export factors prevent R-loop formation, while ubiquitously-expressed specific ribonucleases and DNA-RNA helicases resolve DNA-RNA hybrids...
June 27, 2017: Genes
https://www.readbyqxmd.com/read/28649985/attenuation-of-rna-polymerase-ii-pausing-mitigates-brca1-associated-r-loop-accumulation-and-tumorigenesis
#10
Xiaowen Zhang, Huai-Chin Chiang, Yao Wang, Chi Zhang, Sabrina Smith, Xiayan Zhao, Sreejith J Nair, Joel Michalek, Ismail Jatoi, Meeghan Lautner, Boyce Oliver, Howard Wang, Anna Petit, Teresa Soler, Joan Brunet, Francesca Mateo, Miguel Angel Pujana, Elizabeth Poggi, Krysta Chaldekas, Claudine Isaacs, Beth N Peshkin, Oscar Ochoa, Frederic Chedin, Constantine Theoharis, Lu-Zhe Sun, Tyler J Curiel, Richard Elledge, Victor X Jin, Yanfen Hu, Rong Li
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers...
June 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28641942/the-top1-paradox-friend-and-foe-of-the-eukaryotic-genome
#11
REVIEW
Nayun Kim, Sue Jinks-Robertson
Topoisomerases manage the torsional stress associated with the separation of DNA strands during transcription and DNA replication. Eukaryotic Topoisomerase I (Top1) is a Type IB enzyme that nicks and rejoins only one strand of duplex DNA, and it is especially important during transcription. By resolving transcription-associated torsional stress, Top1 reduces the accumulation of genome-destabilizing R-loops and non-B DNA structures. The DNA nicking activity of Top1, however, can also initiate genome instability in the form of illegitimate recombination, homologous recombination and mutagenesis...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28606110/a-c9orf72-bac-mouse-model-recapitulates-key-epigenetic-perturbations-of-als-ftd
#12
Rustam Esanov, Gabriela Toro Cabrera, Nadja S Andrade, Tania F Gendron, Robert H Brown, Michael Benatar, Claes Wahlestedt, Christian Mueller, Zane Zeier
BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal and progressive neurodegenerative disorder with identified genetic causes representing a significant minority of all cases. A GGGGCC hexanucleotide repeat expansion (HRE) mutation within the C9ORF72 gene has recently been identified as the most frequent known cause of ALS. The expansion leads to partial heterochromatinization of the locus, yet mutant RNAs and dipeptide repeat proteins (DPRs) are still produced in sufficient quantities to confer neurotoxicity...
June 12, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28594954/the-monoclonal-s9-6-antibody-exhibits-highly-variable-binding-affinities-towards-different-r-loop-sequences
#13
Fabian König, Thomas Schubert, Gernot Längst
The monoclonal antibody S9.6 is a widely-used tool to purify, analyse and quantify R-loop structures in cells. A previous study using the surface plasmon resonance technology and a single-chain variable fragment (scFv) of S9.6 showed high affinity (0.6 nM) for DNA-RNA and also a high affinity (2.7 nM) for RNA-RNA hybrids. We used the microscale thermophoresis method allowing surface independent interaction studies and electromobility shift assays to evaluate additional RNA-DNA hybrid sequences and to quantify the binding affinities of the S9...
2017: PloS One
https://www.readbyqxmd.com/read/28587229/ataxin-2-from-rna-control-to-human-health-and-disease
#14
REVIEW
Lauren A Ostrowski, Amanda C Hall, Karim Mekhail
RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures...
June 5, 2017: Genes
https://www.readbyqxmd.com/read/28575672/a-class-of-environmental-and-endogenous-toxins-induces-brca2-haploinsufficiency-and-genome-instability
#15
Shawn Lu Wen Tan, Saakshi Chadha, Yansheng Liu, Evelina Gabasova, David Perera, Karim Ahmed, Stephanie Constantinou, Xavier Renaudin, MiYoung Lee, Ruedi Aebersold, Ashok R Venkitaraman
Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde...
June 1, 2017: Cell
https://www.readbyqxmd.com/read/28575656/histone-mutants-separate-r-loop-formation-from-genome-instability-induction
#16
Desiré García-Pichardo, Juan C Cañas, María L García-Rubio, Belén Gómez-González, Ana G Rondón, Andrés Aguilera
R loops have positive physiological roles, but they can also be deleterious by causing genome instability, and the mechanisms for this are unknown. Here we identified yeast histone H3 and H4 mutations that facilitate R loops but do not cause instability. R loops containing single-stranded DNA (ssDNA), versus RNA-DNA hybrids alone, were demonstrated using ssDNA-specific human AID and bisulfite. Notably, they are similar size regardless of whether or not they induce genome instability. Contrary to mutants causing R loop-mediated instability, these histone mutants do not accumulate H3 serine-10 phosphate (H3S10-P)...
June 1, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28574479/r-loops-in-the-regulation-of-antibody-gene-diversification
#17
REVIEW
Rushad Pavri
For nearly three decades, R loops have been closely linked with class switch recombination (CSR), the process that generates antibody isotypes and that occurs via a complex cascade initiated by transcription-coupled mutagenesis in switch recombination sequences. R loops form during transcription of switch recombination sequences in vitro and in vivo, and there is solid evidence that R loops are required for efficient class switching. The classical model of R loops posits that they boost mutation rates by generating stable and long tracts of single-stranded DNA that serve as the substrate for activation induced deaminase (AID), the enzyme that initiates the CSR reaction cascade by co-transcriptionally mutating ssDNA in switch recombination sequences...
June 2, 2017: Genes
https://www.readbyqxmd.com/read/28562584/structure-of-the-cpf1-endonuclease-r-loop-complex-after-target-dna-cleavage
#18
Stefano Stella, Pablo Alcón, Guillermo Montoya
Cpf1 is an RNA-guided endonuclease that is emerging as a powerful genome-editing tool. Here we provide insight into its DNA-targeting mechanism by determining the structure of Francisella novicida Cpf1 with the triple-stranded R-loop generated after DNA cleavage. The structure reveals the machinery involved in DNA unwinding to form a CRISPR RNA (crRNA)-DNA hybrid and a displaced DNA strand. The protospacer adjacent motif (PAM) is recognized by the PAM-interacting domain. The loop-lysine helix-loop motif in this domain contains three conserved lysine residues that are inserted in a dentate manner into the double-stranded DNA...
June 22, 2017: Nature
https://www.readbyqxmd.com/read/28559482/a-screen-for-rfah-suppressors-reveals-a-key-role-for-a-connector-region-of-termination-factor-rho
#19
Kuang Hu, Irina Artsimovitch
RfaH activates horizontally acquired operons that encode lipopolysaccharide core components, pili, toxins, and capsules. Unlike its paralog NusG, which potentiates Rho-mediated silencing, RfaH strongly inhibits Rho. RfaH is recruited to its target operons via a network of contacts with an elongating RNA polymerase (RNAP) and a specific DNA element called ops to modify RNAP into a pause- and NusG-resistant state. rfaH null mutations confer hypersensitivity to antibiotics and detergents, altered susceptibility to bacteriophages, and defects in virulence...
May 30, 2017: MBio
https://www.readbyqxmd.com/read/28539829/multifaceted-regulation-of-gene-expression-by-the-apoptosis-and-splicing-associated-protein-complex-and-its-components
#20
REVIEW
Bhagyashree Deka, Kusum Kumari Singh
The differential deposition of RNA-binding proteins (RBPs) on pre-mRNA mediates the processes of gene expression. One of the complexes containing RBPs that play a crucial part in RNA metabolism is the apoptosis-and splicing-associated protein (ASAP) complex. In this review, we present a summary of the structure of ASAP complex and its localization. Also, we discuss the findings by different groups on various functions of the subunits of the ASAP complex in RNA metabolism. The subunits of the ASAP complex are RNPS1, Acinus and SAP18...
2017: International Journal of Biological Sciences
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