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"R-loops"

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https://www.readbyqxmd.com/read/29917162/n-terminal-domain-of-human-uracil-dna-glycosylase-hung2-promotes-targeting-to-uracil-sites-adjacent-to-ssdna-dsdna-junctions
#1
Brian P Weiser, Gaddiel Rodriguez, Philip A Cole, James T Stivers
The N-terminal domain (NTD) of nuclear human uracil DNA glycosylase (hUNG2) assists in targeting hUNG2 to replication forks through specific interactions with replication protein A (RPA). Here, we explored hUNG2 activity in the presence and absence of RPA using substrates with ssDNA-dsDNA junctions that mimic structural features of the replication fork and transcriptional R-loops. We find that when RPA is tightly bound to the ssDNA overhang of junction DNA substrates, base excision by hUNG2 is strongly biased toward uracils located 21 bp or less from the ssDNA-dsDNA junction...
June 18, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29916023/senataxin-a-novel-helicase-at-the-interface-of-rna-transcriptome-regulation-and-neurobiology-from-normal-function-to-pathological-roles-in-motor-neuron-disease-and-cerebellar-degeneration
#2
Craig L Bennett, Albert R La Spada
Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4...
2018: Advances in Neurobiology
https://www.readbyqxmd.com/read/29902117/nrde-2-the-human-homolog-of-fission-yeast-nrl1-prevents-dna-damage-accumulation-in-human-cells
#3
Patricia Richard, Koichi Ogami, Yaqiong Chen, Shuang Feng, James J Moresco, John R Yates, James L Manley
The RNA helicase Mtr4 is a versatile protein that is a crucial component of several distinct RNA surveillance complexes. Here we describe a novel complex that contains Mtr4, but has a role distinct from any of those previously described. We found that Mtr4 association with the human homolog of fission yeast Nrl1, NRDE-2, defines a novel function for Mtr4 in the DNA damage response (DDR) pathway. We provide biochemical evidence that Mtr4 and NRDE-2 are part of the same complex and show that both proteins play a role in the DDR by maintaining low DNA double-strand break levels...
June 14, 2018: RNA Biology
https://www.readbyqxmd.com/read/29898919/overexpression-of-pp1-nipp1-limits-the-repair-capacity-of-dna-double-strand-breaks
#4
Claudia Winkler, Raphael Rouget, Dan Wu, Monique Beullens, Aleyde Van Eynde, Mathieu Bollen
The ubiquitously expressed nuclear protein NIPP1 recruits phosphoproteins for regulated dephosphorylation by associated protein phosphatase PP1. To bypass PP1 titration artifacts of NIPP1 overexpression we have engineered covalently linked fusions of PP1 and NIPP1, and demonstrate their potential to selectively explore the function of the PP1:NIPP1 holoenzyme. Using inducible stable cell lines we show that PP1-NIPP1 fusions cause replication stress in a manner that requires both PP1 activity and substrate recruitment via the ForkHead Associated domain of NIPP1...
June 13, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29880725/structure-basis-for-rna-guided-dna-degradation-by-cascade-and-cas3
#5
Yibei Xiao, Min Luo, Adam E Dolan, Maofu Liao, Ailong Ke
Type I CRISPR-Cas system features a sequential target-searching and degradation process on double-stranded DNA, by the RNA-guided Cascade complex and the nuclease-helicase fusion enzyme Cas3, respectively. Here we present a 3.7 Å resolution cryo-EM structure of the Type I-E Cascade/R-loop/Cas3 complex, poised to initiate DNA degradation. Cas3 distinguishes Cascade conformations and only captures the R-loop forming Cascade, to avoid cleaving partially complementary targets. Its nuclease domain recruits the non-target strand (NTS) DNA at a bulged region for the nicking of single-stranded DNA...
June 7, 2018: Science
https://www.readbyqxmd.com/read/29867148/cytosolic-genomic-dna-functions-as-a-natural-antisense
#6
Ken Asada, Keiya Ito, Daishi Yui, Hirokuni Tagaya, Takanori Yokota
Stress conditions such as UV irradiation, exposure to genotoxic agents, stalled DNA replication, and even tumors trigger the release of cytosolic genomic DNA (cgDNA). Classically, cgDNA induces interferon response via its binding to proteins such as STING. In this study, we found previously reported cgDNA (cg721) exists in the cytosol of the mouse cell lines, cultured under no stress conditions. The overexpression of cg721 suppressed the complementary RNA expression using strand selection and knockdown of DNA/RNA hybrid R-loop removing enzyme RNase H and three prime repair exonuclease 1 TREX1 increased the expression levels of cg721 and thus, inhibited the target Naa40 transcript, as well as protein expression, with a phenotypic effect...
June 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29758107/locking-the-non-template-dna-to-control-transcription
#7
Yuri Nedialkov, Dmitri Svetlov, Georgiy A Belogurov, Irina Artsimovitch
Universally conserved NusG/Spt5 factors reduce RNA polymerase pausing and arrest. In a widely accepted model, these proteins bridge the RNA polymerase clamp and lobe domains across the DNA channel, inhibiting the clamp opening to promote pause-free RNA synthesis. However, recent structures of paused transcription elongation complexes show that the clamp does not open and suggest alternative mechanisms of antipausing. Among these mechanisms, direct contacts of NusG/Spt5 proteins with the nontemplate DNA in the transcription bubble have been proposed to prevent unproductive DNA conformations and thus inhibit arrest...
May 14, 2018: Molecular Microbiology
https://www.readbyqxmd.com/read/29742442/rna-dna-hybrid-interactome-identifies-dxh9-as-a-molecular-player-in-transcriptional-termination-and-r-loop-associated-dna-damage
#8
Agnese Cristini, Matthias Groh, Maiken S Kristiansen, Natalia Gromak
R-loops comprise an RNA/DNA hybrid and displaced single-stranded DNA. They play important biological roles and are implicated in pathology. Even so, proteins recognizing these structures are largely undefined. Using affinity purification with the S9.6 antibody coupled to mass spectrometry, we defined the RNA/DNA hybrid interactome in HeLa cells. This consists of known R-loop-associated factors SRSF1, FACT, and Top1, and yet uncharacterized interactors, including helicases, RNA processing, DNA repair, and chromatin factors...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29731414/rna-helicase-ddx1-converts-rna-g-quadruplex-structures-into-r-loops-to-promote-igh-class-switch-recombination
#9
Claudia Ribeiro de Almeida, Somdutta Dhir, Ashish Dhir, Amin E Moghaddam, Quentin Sattentau, Anton Meinhart, Nicholas J Proudfoot
Class switch recombination (CSR) at the immunoglobulin heavy-chain (IgH) locus is associated with the formation of R-loop structures over switch (S) regions. While these often occur co-transcriptionally between nascent RNA and template DNA, we now show that they also form as part of a post-transcriptional mechanism targeting AID to IgH S-regions. This depends on the RNA helicase DDX1 that is also required for CSR in vivo. DDX1 binds to G-quadruplex (G4) structures present in intronic switch transcripts and converts them into S-region R-loops...
April 30, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29674319/long-repeating-ttaggg-n-single-stranded-dna-self-condenses-into-compact-beaded-filaments-stabilized-by-g-quadruplex-formation
#10
Anirban Kar, Nathan Jones, N Özlem Arat, Richard Fishel, Jack Griffith
Conformations adopted by long stretches of single stranded DNA (ssDNA) are of central interest in understanding the architecture of replication forks, R loops, and other structures generated during DNA metabolism in vivo. This is particularly so if the ssDNA consists of short nucleotide repeats. Such studies have been hampered by the lack of defined substrates greater than ~150 nt, and the absence of high-resolution biophysical approaches. Here we describe the generation of very long ssDNA consisting of the mammalian telomeric repeat (5'-TTAGGG-3')n as well as the interrogation of its structure by electron microscopy (EM) and single molecule magnetic tweezers (smMT)...
April 19, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29658469/-r-loop-associated-genetic-instability-why-introns-matter
#11
Benoit Palancade
No abstract text is available yet for this article.
April 2018: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/29657305/strengths-and-weaknesses-of-the-current-strategies-to-map-and-characterize-r-loops
#12
REVIEW
Vincent Vanoosthuyse
R-loops are evolutionarily conserved three-stranded structures that result from the formation of stable DNA:RNA hybrids in the genome. R-loops have attracted increasing interest in recent years as potent regulators of gene expression and genome stability. In particular, their strong association with severe replication stress makes them potential oncogenic structures. Despite their importance, the rules that govern their formation and their dynamics are still controversial and an in-depth description of their direct impact on chromatin organization and DNA transactions is still lacking...
March 27, 2018: Non-Coding RNA
https://www.readbyqxmd.com/read/29629374/rna-surveillance-by-the-nuclear-rna-exosome-mechanisms-and-significance
#13
Koichi Ogami, Yaqiong Chen, James L Manley
The nuclear RNA exosome is an essential and versatile machinery that regulates maturation and degradation of a huge plethora of RNA species. The past two decades have witnessed remarkable progress in understanding the whole picture of its RNA substrates and the structural basis of its functions. In addition to the exosome itself, recent studies focusing on associated co-factors have been elucidating how the exosome is directed towards specific substrates. Moreover, it has been gradually realized that loss-of-function of exosome subunits affect multiple biological processes such as the DNA damage response, R-loop resolution, maintenance of genome integrity, RNA export, translation and cell differentiation...
2018: Non-Coding RNA
https://www.readbyqxmd.com/read/29622660/rnase-h-eliminates-r-loops-that-disrupt-dna-replication-but-is-nonessential-for-efficient-dsb-repair
#14
Hongchang Zhao, Min Zhu, Oliver Limbo, Paul Russell
In Saccharomyces cerevisiae , genome stability depends on RNases H1 and H2, which remove ribonucleotides from DNA and eliminate RNA-DNA hybrids (R-loops). In Schizosaccharomyces pombe , RNase H enzymes were reported to process RNA-DNA hybrids produced at a double-strand break (DSB) generated by I-PpoI meganuclease. However, it is unclear if RNase H is generally required for efficient DSB repair in fission yeast, or whether it has other genome protection roles. Here, we show that S. pombe rnh1∆ rnh201∆ cells, which lack the RNase H enzymes, accumulate R-loops and activate DNA damage checkpoints...
May 2018: EMBO Reports
https://www.readbyqxmd.com/read/29617652/multifaceted-impact-of-microrna-493-5p-on-genome-stabilizing-pathways-induces-platinum-and-parp-inhibitor-resistance-in-brca2-mutated-carcinomas
#15
Khyati Meghani, Walker Fuchs, Alexandre Detappe, Pascal Drané, Ewa Gogola, Sven Rottenberg, Jos Jonkers, Ursula Matulonis, Elizabeth M Swisher, Panagiotis A Konstantinopoulos, Dipanjan Chowdhury
BRCA1/2-mutated ovarian cancers (OCs) are defective in homologous recombination repair (HRR) of double-strand breaks (DSBs) and thereby sensitive to platinum and PARP inhibitors (PARPis). Multiple PARPis have recently received US Food and Drug Administration (FDA) approval for treatment of OCs, and resistance to PARPis is a major clinical problem. Utilizing primary and recurrent BRCA1/2-mutated carcinomas from OC patients, patient-derived lines, and an in vivo BRCA2-mutated mouse model, we identified a microRNA, miR-493-5p, that induced platinum/PARPi resistance exclusively in BRCA2-mutated carcinomas...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29600804/author-correction-attenuation-of-rna-polymerase-ii-pausing-mitigates-brca1-associated-r-loop-accumulation-and-tumorigenesis
#16
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
This corrects the article DOI: 10.1038/ncomms15908.
March 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/29584802/perturbed-autophagy-and-dna-repair-converge-to-promote-neurodegeneration-in-amyotrophic-lateral-sclerosis-and-dementia
#17
Callum Walker, Sherif F El-Khamisy
Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration...
May 1, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29549141/ewing-sarcomas-phenocopy-brca1-deficient-tumors
#18
(no author information available yet)
Transcriptional dysregulation promotes R-loops and impairs homologous recombination in Ewing sarcoma.
May 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29513652/ews-fli1-increases-transcription-to-cause-r-loops-and-block-brca1-repair-in-ewing-sarcoma
#19
Aparna Gorthi, July Carolina Romero, Eva Loranc, Lin Cao, Liesl A Lawrence, Elicia Goodale, Amanda Balboni Iniguez, Xavier Bernard, V Pragathi Masamsetti, Sydney Roston, Elizabeth R Lawlor, Jeffrey A Toretsky, Kimberly Stegmaier, Stephen L Lessnick, Yidong Chen, Alexander J R Bishop
Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress...
March 15, 2018: Nature
https://www.readbyqxmd.com/read/29474582/genome-wide-relationship-between-r-loop-formation-and-antisense-transcription-in-escherichia-coli
#20
Nalini Raghunathan, Rajvardhan M Kapshikar, Jakku K Leela, Jillella Mallikarjun, Philippe Bouloc, Jayaraman Gowrishankar
Transcription termination by Rho is essential for viability in various bacteria, including some major pathogens. Since Rho acts by targeting nascent RNAs that are not simultaneously translated, it also regulates antisense transcription. Here we show that RNase H-deficient mutants of Escherichia coli exhibit heightened sensitivity to the Rho inhibitor bicyclomycin, and that Rho deficiency provokes increased formation of RNA-DNA hybrids (R-loops) which is ameliorated by expression of the phage T4-derived R-loop helicase UvsW...
February 21, 2018: Nucleic Acids Research
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