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"R-loops"

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https://www.readbyqxmd.com/read/28641942/the-top1-paradox-friend-and-foe-of-the-eukaryotic-genome
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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...
May 31, 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
#9
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
#10
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
https://www.readbyqxmd.com/read/28529475/fragile-x-associated-tremor-ataxia-syndrome-from-molecular-pathogenesis-to-development-of-therapeutics
#11
REVIEW
Ha Eun Kong, Juan Zhao, Shunliang Xu, Peng Jin, Yan Jin
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a premutation CGG repeat expansion (55-200 repeats) within the 5' UTR of the fragile X gene (FMR1). FXTAS is characterized by intension tremor, cerebellar ataxia, progressive neurodegeneration, parkinsonism and cognitive decline. The development of transgenic mouse and Drosophila melanogaster models carrying an expanded CGG repeat has yielded valuable insight into the pathophysiology of FXTAS. To date, we know of two main molecular mechanisms of this disorder: (1) a toxic gain of function of the expanded CGG-repeat FMR1 mRNA, which results in the binding/sequestration of the CGG-binding proteins; and (2) CGG repeat-associated non-AUG-initiated (RAN) translation, which generates a polyglycine peptide toxic to cells...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28498974/strong-transcription-blockage-mediated-by-r-loop-formation-within-a-g-rich-homopurine-homopyrimidine-sequence-localized-in-the-vicinity-of-the-promoter
#12
Boris P Belotserkovskii, Jane Hae Soo Shin, Philip C Hanawalt
Guanine-rich (G-rich) homopurine-homopyrimidine nucleotide sequences can block transcription with an efficiency that depends upon their orientation, composition and length, as well as the presence of negative supercoiling or breaks in the non-template DNA strand. We report that a G-rich sequence in the non-template strand reduces the yield of T7 RNA polymerase transcription by more than an order of magnitude when positioned close (9 bp) to the promoter, in comparison to that for a distal (∼250 bp) location of the same sequence...
May 11, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28487353/the-chromatin-remodelling-factor-atrx-suppresses-r-loops-in-transcribed-telomeric-repeats
#13
Diu Tt Nguyen, Hsiao Phin J Voon, Barbara Xella, Caroline Scott, David Clynes, Christian Babbs, Helena Ayyub, Jon Kerry, Jacqueline A Sharpe, Jackie A Sloane-Stanley, Sue Butler, Chris A Fisher, Nicki E Gray, Thomas Jenuwein, Douglas R Higgs, Richard J Gibbons
ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n ATRX mutations are found in nearly all tumours that maintain their telomeres via the alternative lengthening of telomere (ALT) pathway, and ATRX is known to suppress this pathway. Here, we show that recruitment of ATRX to telomeric repeats depends on repeat number, orientation and, critically, on repeat transcription. Importantly, the transcribed telomeric repeats form RNA-DNA hybrids (R-loops) whose abundance correlates with the recruitment of ATRX Here, we show loss of ATRX is also associated with increased R-loop formation...
June 2017: EMBO Reports
https://www.readbyqxmd.com/read/28481984/the-dna-damage-response-ddr-is-induced-by-the-c9orf72-repeat-expansion-in-amyotrophic-lateral-sclerosis
#14
Manal A Farg, Anna Konopka, Kai Ying Soo, Daisuke Ito, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease affecting motor neurons. Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9orf72 are the major cause of familial ALS and frontotemporal dementia (FTD) worldwide. The C9orf72 repeat expansion undergoes repeat-associated non-ATG (RAN) translation to produce five dipeptide repeat proteins (DRPs), including poly(GR) and poly(PR). Whilst it remains unclear how mutations in C9orf72 lead to neurodegeneration in ALS/FTD, dysfunction to the nucleolus and R loop formation are implicated as pathogenic mechanisms...
May 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28477131/noncanonical-atm-activation-and-signaling-in-response-to-transcription-blocking-dna-damage
#15
Jurgen A Marteijn, Wim Vermeulen, Maria Tresini
Environmental genotoxins and metabolic byproducts generate DNA lesions that can cause genomic instability and disrupt tissue homeostasis. To ensure genomic integrity, cells employ mechanisms that convert signals generated by stochastic DNA damage into organized responses, including activation of repair systems, cell cycle checkpoints, and apoptotic mechanisms. DNA damage response (DDR) signaling pathways coordinate these responses and determine cellular fates in part, by transducing signals that modulate RNA metabolism...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28471430/dna-rna-hybrids-the-risks-of-dna-breakage-during-transcription
#16
Andrés Aguilera, Belén Gómez-González
Although R loops can occur at different genomic locations, the factors that determine their formation and frequency remain unclear. Emerging evidence indicates that DNA breaks stimulate DNA-RNA hybrid formation. Here, we discuss the possibility that formation of hybrids may be an inevitable risk of DNA breaks that occur within actively transcribed regions. While such hybrids must be removed to permit repair, their potential role as repair intermediates remains to be established.
May 4, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28447783/real-time-detection-reveals-responsive-cotranscriptional-formation-of-persistent-intramolecular-dna-and-intermolecular-dna-rna-hybrid-g-quadruplexes-stabilized-by-r-loop
#17
Yang Zhao, Jia-Yu Zhang, Zong-Yu Zhang, Tan-Jun Tong, Yu-Hua Hao, Zheng Tan
G-quadruplex (GQ) structures are implicated in important physiological and pathological processes. Millions of GQ-forming motifs are enriched near transcription start sites (TSSs) of animal genes. Transcription can induce the formation of GQs, which in turn regulate transcription. The kinetics of the formation and persistence of GQs in transcription is crucial for the role they play but has not yet been explored. We established a method based on the fluorescence resonance energy transfer (FRET) technique to monitor in real-time the cotranscriptional formation and post-transcriptional persistence of GQs in DNA...
June 6, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28437608/crispr-cas9-mediated-dna-unwinding-detected-using-site-directed-spin-labeling
#18
Narin S Tangprasertchai, Rosa Di Felice, Xiaojun Zhang, Ian M Slaymaker, Carolina Vazquez Reyes, Wei Jiang, Remo Rohs, Peter Z Qin
The RNA-guided CRISPR-Cas9 nuclease has revolutionized genome engineering, yet its mechanism for DNA target selection is not fully understood. A crucial step in Cas9 target recognition involves unwinding of the DNA duplex to form a three-stranded R-loop structure. Work reported here demonstrates direct detection of Cas9-mediated DNA unwinding by a combination of site-directed spin labeling and molecular dynamics simulations. The results support a model in which the unwound nontarget strand is stabilized by a positively charged patch located between the two nuclease domains of Cas9 and reveal uneven increases in flexibility along the unwound nontarget strand upon scissions of the DNA backbone...
May 3, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28431230/structural-basis-for-guide-rna-processing-and-seed-dependent-dna-targeting-by-crispr-cas12a
#19
Daan C Swarts, John van der Oost, Martin Jinek
The CRISPR-associated protein Cas12a (Cpf1), which has been repurposed for genome editing, possesses two distinct nuclease activities: endoribonuclease activity for processing its own guide RNAs and RNA-guided DNase activity for target DNA cleavage. To elucidate the molecular basis of both activities, we determined crystal structures of Francisella novicida Cas12a bound to guide RNA and in complex with an R-loop formed by a non-cleavable guide RNA precursor and a full-length target DNA. Corroborated by biochemical experiments, these structures reveal the mechanisms of guide RNA processing and pre-ordering of the seed sequence in the guide RNA that primes Cas12a for target DNA binding...
April 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28429714/pif1-family-dna-helicases-suppress-r-loop-mediated-genome-instability-at-trna-genes
#20
Phong Lan Thao Tran, Thomas J Pohl, Chi-Fu Chen, Angela Chan, Sebastian Pott, Virginia A Zakian
Saccharomyces cerevisiae encodes two Pif1 family DNA helicases, Pif1 and Rrm3. Rrm3 promotes DNA replication past stable protein complexes at tRNA genes (tDNAs). We identify a new role for the Pif1 helicase: promotion of replication and suppression of DNA damage at tDNAs. Pif1 binds multiple tDNAs, and this binding is higher in rrm3Δ cells. Accumulation of replication intermediates and DNA damage at tDNAs is higher in pif1Δ rrm3Δ than in rrm3Δ cells. DNA damage at tDNAs in the absence of these helicases is suppressed by destabilizing R-loops while Pif1 and Rrm3 binding to tDNAs is increased upon R-loop stabilization...
April 21, 2017: Nature Communications
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