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"R-loops"

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https://www.readbyqxmd.com/read/27899586/r-loopdb-a-database-for-r-loop-forming-sequences-rlfs-and-r-loops
#1
Piroon Jenjaroenpun, Thidathip Wongsurawat, Sawannee Sutheeworapong, Vladimir A Kuznetsov
R-loopDB (http://rloop.bii.a-star.edu.sg) was originally constructed as a collection of computationally predicted R-loop forming sequences (RLFSs) in the human genic regions. The renewed R-loopDB provides updates, improvements and new options, including access to recent experimental data. It includes genome-scale prediction of RLFSs for humans, six other animals and yeast. Using the extended quantitative model of RLFSs (QmRLFS), we significantly increased the number of RLFSs predicted in the human genes and identified RLFSs in other organism genomes...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27863397/targeting-gli-by-gant61-involves-mechanisms-dependent-on-inhibition-of-both-transcription-and-dna-licensing
#2
Ruowen Zhang, Jiahui Wu, Sylvain Ferrandon, Katie J Glowacki, Janet A Houghton
The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27851891/traveling-rocky-roads-the-consequences-of-transcription-blocking-dna-lesions-on-rna-polymerase-ii
#3
REVIEW
Barbara Steurer, Jurgen A Marteijn
The faithful transcription of eukaryotic genes by RNA polymerase II (RNAP2) is crucial for proper cell function and tissue homeostasis. However, transcription-blocking DNA lesions of both an endogenous and environmental origin continuously challenge the progression of elongating RNAP2. The stalling of RNAP2 on a transcription-blocking lesion triggers a series of highly regulated events, including RNAP2 processing to make the lesion accessible for DNA repair, R-loop-mediated DNA damage signaling, and the initiation of transcription-coupled DNA repair...
November 13, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27849576/two-familial-als-proteins-function-in-prevention-repair-of-transcription-associated-dna-damage
#4
Sarah J Hill, Daniel A Mordes, Lisa A Cameron, Donna S Neuberg, Serena Landini, Kevin Eggan, David M Livingston
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27846236/disruption-of-higher-order-dna-structures-in-friedreich-s-ataxia-gaa-n-repeats-by-pna-or-lna-targeting
#5
Helen Bergquist, Cristina S J Rocha, Rubén Álvarez-Asencio, Chi-Hung Nguyen, Mark W Rutland, C I Edvard Smith, Liam Good, Peter E Nielsen, Rula Zain
Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich's ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions...
2016: PloS One
https://www.readbyqxmd.com/read/27804953/structural-roles-of-guide-rnas-in-the-nuclease-activity-of-cas9-endonuclease
#6
Youngbin Lim, So Young Bak, Keewon Sung, Euihwan Jeong, Seung Hwan Lee, Jin-Soo Kim, Sangsu Bae, Seong Keun Kim
The type II CRISPR-associated protein Cas9 recognizes and cleaves target DNA with the help of two guide RNAs (gRNAs; tracrRNA and crRNA). However, the detailed mechanisms and kinetics of these gRNAs in the Cas9 nuclease activity are unclear. Here, we investigate the structural roles of gRNAs in the CRISPR-Cas9 system by single-molecule spectroscopy and reveal a new conformation of inactive Cas9 that is thermodynamically more preferable than active apo-Cas9. We find that tracrRNA prevents Cas9 from changing into the inactive form and leads to the Cas9:gRNA complex...
November 2, 2016: Nature Communications
https://www.readbyqxmd.com/read/27796495/transcription-replication-conflicts-at-chromosomal-fragile-sites-consequences-in-m-phase-and-beyond
#7
REVIEW
Vibe H Oestergaard, Michael Lisby
Collision between the molecular machineries responsible for transcription and replication is an important source of genome instability. Certain transcribed regions known as chromosomal fragile sites are particularly prone to recombine and mutate in a manner that correlates with specific transcription and replication patterns. At the same time, these chromosomal fragile sites engage in aberrant DNA structures in mitosis. Here, we discuss the mechanistic details of transcription-replication conflicts including putative scenarios for R-loop-induced replication inhibition to understand how transcription-replication conflicts transition from S phase into various aberrant DNA structures in mitosis...
October 28, 2016: Chromosoma
https://www.readbyqxmd.com/read/27793359/nascent-connections-r-loops-and-chromatin-patterning
#8
REVIEW
Frédéric Chédin
RNA molecules, such as long noncoding RNAs (lncRNAs), have critical roles in regulating gene expression, chromosome architecture, and the modification states of chromatin. Recent developments suggest that RNA also influences gene expression and chromatin patterns through the interaction of nascent transcripts with their DNA template via the formation of co-transcriptional R-loop structures. R-loop formation over specific, conserved, hotspots occurs at thousands of genes in mammalian genomes and represents an important and dynamic feature of mammalian chromatin...
December 2016: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/27787508/dangerous-r-loops-form-in-the-absence-of-h3k9-methylation
#9
Anna Elisabetta Salcini
Methylation of histone H3 on lysine 9 (H3K9) is a hallmark of transcriptionally inactive heterochromatin that is deregulated in pathological conditions. A new study shows that complete loss of H3K9 methylation in Caenorhabditis elegans leads to derepression of repetitive elements and formation of DNA:RNA hybrids (R loops), resulting in increased rates of repeat-specific mutation.
October 27, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27771483/senataxin-genome-guardian-at-the-interface-of-transcription-and-neurodegeneration
#10
Matthias Groh, Laura Oana Albulescu, Agnese Cristini, Natalia Gromak
R-loops comprise an RNA/DNA hybrid and displaced single-stranded DNA. They play crucial biological functions and are implicated in neurological diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia, Fragile X syndrome) and cancer. Currently it is unclear which mechanisms cause R-loops structures to become pathogenic. The RNA/DNA helicase Senataxin (SETX) is one of the best characterised R-loop-binding factors in vivo. Mutations in SETX are linked to two neurodegenerative disorders: ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4)...
October 19, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27725641/increased-global-transcription-activity-as-a-mechanism-of-replication-stress-in-cancer
#11
Panagiotis Kotsantis, Lara Marques Silva, Sarah Irmscher, Rebecca M Jones, Lisa Folkes, Natalia Gromak, Eva Petermann
Cancer is a disease associated with genomic instability that often results from oncogene activation. This in turn leads to hyperproliferation and replication stress. However, the molecular mechanisms that underlie oncogene-induced replication stress are still poorly understood. Oncogenes such as HRAS(V12) promote proliferation by upregulating general transcription factors to stimulate RNA synthesis. Here we investigate whether this increase in transcription underlies oncogene-induced replication stress. We show that in cells overexpressing HRAS(V12), elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which together with R-loop accumulation results in replication fork slowing and DNA damage...
October 11, 2016: Nature Communications
https://www.readbyqxmd.com/read/27700226/lncrnas-bridging-environmental-sensing-and-gene-expression
#12
Zachary T Beck, Zheng Xing, Elizabeth J Tran
The survival of all organisms is dependent on complex, coordinated responses to environmental cues. Non-coding RNAs have been identified as major players in regulation of gene expression, with recent evidence supporting roles for long non-coding (lnc)RNAs in both transcriptional and post-transcriptional control. Evidence from our laboratory shows that lncRNAs have the ability to form hybridized structures called R-loops with specific DNA target sequences in S. cerevisiae, thereby modulating gene expression...
October 4, 2016: RNA Biology
https://www.readbyqxmd.com/read/27668659/histone-h3k9-methylation-is-dispensable-for-caenorhabditis-elegans-development-but-suppresses-rna-dna-hybrid-associated-repeat-instability
#13
Peter Zeller, Jan Padeken, Robin van Schendel, Veronique Kalck, Marcel Tijsterman, Susan M Gasser
Histone H3 lysine 9 (H3K9) methylation is a conserved modification that generally represses transcription. In Caenorhabditis elegans it is enriched on silent tissue-specific genes and repetitive elements. In met-2 set-25 double mutants, which lack all H3K9 methylation (H3K9me), embryos differentiate normally, although mutant adults are sterile owing to extensive DNA-damage-driven apoptosis in the germ line. Transposons and simple repeats are derepressed in both germline and somatic tissues. This unprogrammed transcription correlates with increased rates of repeat-specific insertions and deletions, copy number variation, R loops and enhanced sensitivity to replication stress...
September 26, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27638543/rna-dna-sequence-differences-in-saccharomyces-cerevisiae
#14
Isabel X Wang, Christopher Grunseich, Youree G Chung, Hojoong Kwak, Girish Ramrattan, Zhengwei Zhu, Vivian G Cheung
Alterations of RNA sequences and structures, such as those from editing and alternative splicing, result in two or more RNA transcripts from a DNA template. It was thought that in yeast, RNA editing only occurs in tRNAs. Here, we found that Saccharomyces cerevisiae have all 12 types of RNA-DNA sequence differences (RDDs) in the mRNA. We showed these sequence differences are propagated to proteins, as we identified peptides encoded by the RNA sequences in addition to those by the DNA sequences at RDD sites. RDDs are significantly enriched at regions with R-loops...
November 2016: Genome Research
https://www.readbyqxmd.com/read/27600412/r-loops-and-links-to-human-disease
#15
Patricia Richard, James L Manley
Aberrant R-loop structures are increasingly being realized to be an important contributor to human disease. R loops, which are mainly co-transcriptional, abundant RNA/DNA hybrids, form naturally and can indeed be beneficial for transcription regulation at certain loci. However, their unwanted persistence elsewhere or in particular situations can lead to DNA double-strand breaks, chromosome rearrangements and hypermutation, all sources of genomic instability. Mutations in genes involved in R-loop resolution or mutations leading to R-loop formation at specific genes affect the normal physiology of the cell...
September 3, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27595121/fanconi-anemia-pathway-regulates-convergent-transcription-induced-cell-death-at-trinucleotide-repeats-in-human-cells
#16
Nimrat Chatterjee, Yunfu Lin, John H Wilson
Almost 20 incurable neurodegenerative disorders are caused by trinucleotide repeat (TNR) expansion beyond a certain threshold, with disease time of onset and severity positively correlating with repeat length. Typically, long TNRs display a bias toward further expansion and repeats continue to expand not only during germline transmissions from parents to offspring, but also remain highly unstable in somatic tissues of patients. Hence, understanding TNR instability mechanisms sheds light on underlying disease pathology...
May 2016: Postdoc Journal: a Journal of Postdoctoral Research and Postdoctoral Affairs
https://www.readbyqxmd.com/read/27588603/dna-targeting-by-a-minimal-crispr-rna-guided-cascade
#17
Megan L Hochstrasser, David W Taylor, Jack E Kornfeld, Eva Nogales, Jennifer A Doudna
Bacteria employ surveillance complexes guided by CRISPR (clustered, regularly interspaced, short palindromic repeats) RNAs (crRNAs) to target foreign nucleic acids for destruction. Although most type I and type III CRISPR systems require four or more distinct proteins to form multi-subunit surveillance complexes, the type I-C systems use just three proteins to achieve crRNA maturation and double-stranded DNA target recognition. We show that each protein plays multiple functional and structural roles: Cas5c cleaves pre-crRNAs and recruits Cas7 to position the RNA guide for DNA binding and unwinding by Cas8c...
September 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27574117/intersection-of-calorie-restriction-and-magnesium-in-the-suppression-of-genome-destabilizing-rna-dna-hybrids
#18
Karan J Abraham, Janet N Y Chan, Jayesh S Salvi, Brandon Ho, Amanda Hall, Elva Vidya, Ru Guo, Samuel A Killackey, Nancy Liu, Jeffrey E Lee, Grant W Brown, Karim Mekhail
Dietary calorie restriction is a broadly acting intervention that extends the lifespan of various organisms from yeast to mammals. On another front, magnesium (Mg(2+)) is an essential biological metal critical to fundamental cellular processes and is commonly used as both a dietary supplement and treatment for some clinical conditions. If connections exist between calorie restriction and Mg(2+) is unknown. Here, we show that Mg(2+), acting alone or in response to dietary calorie restriction, allows eukaryotic cells to combat genome-destabilizing and lifespan-shortening accumulations of RNA-DNA hybrids, or R-loops...
October 14, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27552054/co-transcriptional-r-loops-are-the-main-cause-of-estrogen-induced-dna-damage
#19
Caroline Townsend Stork, Michael Bocek, Madzia P Crossley, Julie Sollier, Lionel A Sanz, Frédéric Chédin, Tomek Swigut, Karlene A Cimprich
The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs)...
August 23, 2016: ELife
https://www.readbyqxmd.com/read/27539655/structural-insight-into-c9orf72-hexanucleotide-repeat-expansions-towards-new-therapeutic-targets-in-ftd-als
#20
Vijay Kumar, Tara Kashav, Asimul Islam, Faizan Ahmad, Md Imtaiyaz Hassan
Hexanucleotide repeat expansions, (G4C2) in the C9orf72 gene are considered as the single most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). (G4C2), either as DNA or the transcribed RNA, can folds into unusual secondary structures, including G-quadruplex, R-loop, I-motif and hairpin. These structural polymorphism at both DNA and RNA levels were proposed to initiate molecular cascade leading to ALS/FTD. G-quadruplexes are composed of stacked G4 tetrads, held by hydrophobic bonds, and is highly stable secondary structure...
August 15, 2016: Neurochemistry International
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