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"R-loops"

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https://www.readbyqxmd.com/read/29447396/rna-dna-hybrids-promote-the-expansion-of-friedreich-s-ataxia-gaa-n-repeats-via-break-induced-replication
#1
Alexander J Neil, Miranda U Liang, Alexandra N Khristich, Kartik A Shah, Sergei M Mirkin
Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA-DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich's ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA-DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed...
February 13, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29439150/myelodysplastic-syndrome-splicing-factor-mutations-induce-r-loops
#2
(no author information available yet)
Mutations in SRSF2 and U2AF35 trigger replication stress and ATR activation via R-loop formation.
February 9, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29419415/spliceosomal-components-protect-embryonic-neurons-from-r-loop-mediated-dna-damage-and-apoptosis
#3
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
https://www.readbyqxmd.com/read/29404398/gene-gating-at-nuclear-pores-prevents-the-formation-of-r-loops
#4
Hélène Gaillard, Francisco García-Benítez, Andrés Aguilera
Transcription is an important source of genetic variability. A large amount of transcription-associated genome variation arises from the unscheduled formation of R loops. We have recently found that physical proximity of chromatin to nuclear pores prevents the formation of pathological R loops during transcription. Our study opens new perspectives to understand genome stability as a function of nuclear location.
2018: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29395064/senataxin-mutation-reveals-how-r-loops-promote-transcription-by-blocking-dna-methylation-at-gene-promoters
#5
Christopher Grunseich, Isabel X Wang, Jason A Watts, Joshua T Burdick, Robert D Guber, Zhengwei Zhu, Alan Bruzel, Tyler Lanman, Kelian Chen, Alice B Schindler, Nancy Edwards, Abhik Ray-Chaudhury, Jianhua Yao, Tanya Lehky, Grzegorz Piszczek, Barbara Crain, Kenneth H Fischbeck, Vivian G Cheung
R-loops are three-stranded nucleic acid structures found abundantly and yet often viewed as by-products of transcription. Studying cells from patients with a motor neuron disease (amyotrophic lateral sclerosis 4 [ALS4]) caused by a mutation in senataxin, we uncovered how R-loops promote transcription. In ALS4 patients, the senataxin mutation depletes R-loops with a consequent effect on gene expression. With fewer R-loops in ALS4 cells, the expression of BAMBI, a negative regulator of transforming growth factor β (TGF-β), is reduced; that then leads to the activation of the TGF-β pathway...
February 1, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29395063/the-augmented-r-loop-is-a-unifying-mechanism-for-myelodysplastic-syndromes-induced-by-high-risk-splicing-factor-mutations
#6
Liang Chen, Jia-Yu Chen, Yi-Jou Huang, Ying Gu, Jinsong Qiu, Hao Qian, Changwei Shao, Xuan Zhang, Jing Hu, Hairi Li, Shunmin He, Yu Zhou, Omar Abdel-Wahab, Dong-Er Zhang, Xiang-Dong Fu
Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway...
February 1, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29394375/replication-stress-induces-accumulation-of-fancd2-at-central-region-of-large-fragile-genes
#7
Yusuke Okamoto, Watal M Iwasaki, Kazuto Kugou, Kazuki K Takahashi, Arisa Oda, Koichi Sato, Wataru Kobayashi, Hidehiko Kawai, Ryo Sakasai, Akifumi Takaori-Kondo, Takashi Yamamoto, Masato T Kanemaki, Masato Taoka, Toshiaki Isobe, Hitoshi Kurumizaka, Hideki Innan, Kunihiro Ohta, Masamichi Ishiai, Minoru Takata
During mild replication stress provoked by low dose aphidicolin (APH) treatment, the key Fanconi anemia protein FANCD2 accumulates on common fragile sites, observed as sister foci, and protects genome stability. To gain further insights into FANCD2 function and its regulatory mechanisms, we examined the genome-wide chromatin localization of FANCD2 in this setting by ChIP-seq analysis. We found that FANCD2 mostly accumulates in the central regions of a set of large transcribed genes that were extensively overlapped with known CFS...
January 31, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29386125/brca2-regulates-transcription-elongation-by-rna-polymerase-ii-to-prevent-r-loop-accumulation
#8
Mahmud K K Shivji, Xavier Renaudin, Çiğdem H Williams, Ashok R Venkitaraman
The controlled release of RNA polymerase II (RNAPII) from promoter-proximal pausing (PPP) sites is critical for transcription elongation in metazoans. We show that the human tumor suppressor BRCA2 interacts with RNAPII to regulate PPP release, thereby preventing unscheduled RNA-DNA hybrids (R-loops) implicated in genomic instability and carcinogenesis. BRCA2 inactivation by depletion or cancer-causing mutations instigates RNAPII accumulation and R-loop accrual at PPP sites in actively transcribed genes, accompanied by γH2AX formation marking DNA breakage, which is reduced by ERCC4 endonuclease depletion...
January 23, 2018: Cell Reports
https://www.readbyqxmd.com/read/29358759/trf1-participates-in-chromosome-end-protection-by-averting-trf2-dependent-telomeric-r-loops
#9
Yong Woo Lee, Rajika Arora, Harry Wischnewski, Claus M Azzalin
The shelterin protein TRF2 assembles protective T loops at chromosome ends by stimulating intramolecular invasion of the telomeric G-rich single-stranded DNA (ssDNA) overhang into the duplex telomeric array. The other shelterin factor, TRF1, is thought to mainly facilitate telomeric dsDNA replication without directly participating in end protection. Here we show that in vitro human TRF2 stimulates invasion of G-rich TERRA-like RNA into telomeric dsDNA, leading to formation of telomeric RNA-DNA hybrids (telR loops)...
January 22, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29357316/a-novel-mode-for-transcription-inhibition-mediated-by-pna-induced-r-loops-with-a-model-in-vitro-system
#10
Alicia D D'Souza, Boris P Belotserkovskii, Philip C Hanawalt
The selective inhibition of transcription of a chosen gene by an artificial agent has numerous applications. Usually, these agents are designed to bind a specific nucleotide sequence in the promoter or within the transcribed region of the chosen gene. However, since optimal binding sites might not exist within the gene, it is of interest to explore the possibility of transcription inhibition when the agent is designed to bind at other locations. One of these possibilities arises when an additional transcription initiation site (e...
January 18, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29327083/r-loops-targets-for-nuclease-cleavage-and-repeat-instability
#11
REVIEW
Catherine H Freudenreich
R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias...
January 11, 2018: Current Genetics
https://www.readbyqxmd.com/read/29320733/dna-unwinding-is-the-primary-determinant-of-crispr-cas9-activity
#12
Shanzhong Gong, Helen Hong Yu, Kenneth A Johnson, David W Taylor
Bacterial adaptive immunity utilizes RNA-guided surveillance complexes comprising Cas proteins together with CRISPR RNAs (crRNAs) to target foreign nucleic acids for destruction. Cas9, a type II CRISPR-Cas effector complex, can be programed with a single-guide RNA that base pairs with the target strand of dsDNA, displacing the non-target strand to create an R-loop, where the HNH and the RuvC nuclease domains cleave opposing strands. While many structural and biochemical studies have shed light on the mechanism of Cas9 cleavage, a clear unifying model has yet to emerge...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29298824/mof-suppresses-replication-stress-and-contribute-to-resolution-of-stalled-replication-forks
#13
Dharmendra Kumar Singh, Raj K Pandita, Mayank Singh, Sharmistha Chakraborty, Shashank Hambarde, Deepti Ramnarain, Vijaya Charaka, Kazi Mokim Ahmed, Clayton R Hunt, Tej K Pandita
The hMOF protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation, however its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted for MOF and under replicative stress induced by cisplatin, hydroxyurea or camptothecin have reduced survival, a higher frequency of S-phase specific chromosome damage and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing...
January 3, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29289567/the-affinity-of-the-s9-6-antibody-for-double-stranded-rnas-impacts-the-accurate-mapping-of-r-loops-in-fission-yeast
#14
Stella R Hartono, Amélie Malapert, Pénélope Legros, Pascal Bernard, Frédéric Chédin, Vincent Vanoosthuyse
No abstract text is available yet for this article.
December 28, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29248492/r-loops-cause-genomic-instability-in-wiskott-aldrich-syndrome-thelper-lymphocytes
#15
Koustav Sarkar, Seong-Su Han, Kuo-Kwang Wen, Hans D Ochs, Loïc Dupré, Michael M Seidman, Yatin M Vyas
BACKGROUND: Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN), caused by WAS mutations affecting WASp expression or activity, manifest in immunodeficiency, autoimmunity, genomic-instability, and lymphoid-cancer. WASp supports filamentous-actin formation in the cytoplasm and gene-transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined...
December 14, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29179918/when-dna-topology-turns-deadly-rna-polymerases-dig-in-their-r-loops-to-stand-their-ground-new-positive-and-negative-super-twists-in-the-replication-transcription-conflict
#16
REVIEW
Andrei Kuzminov
Head-on replication-transcription conflict is especially bitter in bacterial chromosomes, explaining why actively transcribed genes are always co-oriented with replication. The mechanism of this conflict remains unclear, besides the anticipated accumulation of positive supercoils between head-on-conflicting polymerases. Unexpectedly, experiments in bacterial and human cells reveal that head-on replication-transcription conflict induces R-loops, indicating hypernegative supercoiling [(-)sc] in the region - precisely the opposite of that assumed...
November 24, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/29177737/immunoprecipitation-of-rna-dna-hybrids-from-budding-yeast
#17
Aziz El Hage, David Tollervey
During transcription, the nascent transcript behind an elongating RNA polymerase (RNAP) can invade the DNA duplex and hybridize with the complementary DNA template strand, generating a three-stranded "R-loop" structure, composed of an RNA:DNA duplex and an unpaired non-template DNA strand. R-loops can be strongly associated with actively transcribed loci by all RNAPs including the mitochondrial RNA polymerase (mtRNAP). In this chapter, we describe two protocols for the detection of RNA:DNA hybrids in living budding yeast cells, one that uses conventional chromatin immunoprecipitation (ChIP-qPCR) and one that uses DNA:RNA immunoprecipitation (DRIP-qPCR)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29177731/topoisomerase-i-and-genome-stability-the-good-and-the-bad
#18
Jang-Eun Cho, Sue Jinks-Robertson
Topoisomerase I (Top1) resolves torsional stress that accumulates during transcription, replication and chromatin remodeling by introducing a transient single-strand break in DNA. The cleavage activity of Top1 has opposing roles, either promoting or destabilizing genome integrity depending on the context. Resolution of transcription-associated negative supercoils, for example, prevents pairing of the nascent RNA with the DNA template (R-loops) as well as DNA secondary structure formation. Reduced Top1 levels thus enhance CAG repeat contraction, somatic hypermutation, and class switch recombination...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29170278/a-mitosis-specific-and-r-loop-driven-atr-pathway-promotes-faithful-chromosome-segregation
#19
Lilian Kabeche, Hai Dang Nguyen, Remi Buisson, Lee Zou
The ATR kinase is crucial for DNA damage and replication stress responses. Here, we describe a surprising role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered CDK1 activity, DNA damage responses, or unscheduled DNA synthesis, but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A-regulated association with CENP-F, allowing ATR to engage RPA-coated centromeric R loops...
November 23, 2017: Science
https://www.readbyqxmd.com/read/29162938/rna-metabolism-is-the-primary-target-of-formamide-in-vivo
#20
Rafael Hoyos-Manchado, Félix Reyes-Martín, Charalampos Rallis, Enrique Gamero-Estévez, Pablo Rodríguez-Gómez, Juan Quintero-Blanco, Jürg Bähler, Juan Jiménez, Víctor A Tallada
The synthesis, processing and function of coding and non-coding RNA molecules and their interacting proteins has been the focus of a great deal of research that has boosted our understanding of key molecular pathways that underlie higher order events such as cell cycle control, development, innate immune response and the occurrence of genetic diseases. In this study, we have found that formamide preferentially weakens RNA related processes in vivo. Using a non-essential Schizosaccharomyces pombe gene deletion collection, we identify deleted loci that make cells sensitive to formamide...
November 21, 2017: Scientific Reports
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