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https://www.readbyqxmd.com/read/29327083/r-loops-targets-for-nuclease-cleavage-and-repeat-instability
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/29145633/the-initiation-propagation-and-dynamics-of-crispr-spycas9-r-loop-complex
#11
Yan Zeng, Yang Cui, Yong Zhang, Yanruo Zhang, Meng Liang, Hui Chen, Jie Lan, Guangtao Song, Jizhong Lou
CRISPR-Cas9 system has been widely used for efficient genome editing. Although the structures of Cas9 protein in complex with single-guided RNA (sgRNA) and target DNA have been resolved, the molecular details about the formation of Cas9 endonuclease R-loop structure remain elusive. Here we examine the DNA cleavage activities of Streptococcus pyogenes Cas9 (SpyCas9) and its mutants using various target sequences and study the conformational dynamics of R-loop structure during target binding using single-molecule fluorescence energy transfer (smFRET) technique...
November 14, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29129920/transcription-putting-r-loops-firmly-on-the-map
#12
Katharine H Wrighton
No abstract text is available yet for this article.
November 13, 2017: Nature Reviews. Genetics
https://www.readbyqxmd.com/read/29104020/r-chip-using-inactive-rnase-h-reveals-dynamic-coupling-of-r-loops-with-transcriptional-pausing-at-gene-promoters
#13
Liang Chen, Jia-Yu Chen, Xuan Zhang, Ying Gu, Rui Xiao, Changwei Shao, Peng Tang, Hao Qian, Daji Luo, Hairi Li, Yu Zhou, Dong-Er Zhang, Xiang-Dong Fu
R-loop, a three-stranded RNA/DNA structure, has been linked to induced genome instability and regulated gene expression. To enable precision analysis of R-loops in vivo, we develop an RNase-H-based approach; this reveals predominant R-loop formation near gene promoters with strong G/C skew and propensity to form G-quadruplex in non-template DNA, corroborating with all biochemically established properties of R-loops. Transcription perturbation experiments further indicate that R-loop induction correlates to transcriptional pausing...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29103969/differentiation-of-human-induced-pluripotent-or-embryonic-stem-cells-decreases-the-dna-damage-repair-by-homologous-recombination
#14
Kalpana Mujoo, Raj K Pandita, Anjana Tiwari, Vijay Charaka, Sharmistha Chakraborty, Dharmendra Kumar Singh, Shashank Hambarde, Walter N Hittelman, Nobuo Horikoshi, Clayton R Hunt, Kum Kum Khanna, Alexander Y Kots, E Brian Butler, Ferid Murad, Tej K Pandita
The nitric oxide (NO)-cyclic GMP pathway contributes to human stem cell differentiation, but NO free radical production can also damage DNA, necessitating a robust DNA damage response (DDR) to ensure cell survival. How the DDR is affected by differentiation is unclear. Differentiation of stem cells, either inducible pluripotent or embryonic derived, increased residual DNA damage as determined by γ-H2AX and 53BP1 foci, with increased S-phase-specific chromosomal aberration after exposure to DNA-damaging agents, suggesting reduced homologous recombination (HR) repair as supported by the observation of decreased HR-related repair factor foci formation (RAD51 and BRCA1)...
November 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29074626/human-tho-sin3a-interaction-reveals-new-mechanisms-to-prevent-r-loops-that-cause-genome%C3%A2-instability
#15
Irene Salas-Armenteros, Carmen Pérez-Calero, Aleix Bayona-Feliu, Emanuela Tumini, Rosa Luna, Andrés Aguilera
R-loops, formed by co-transcriptional DNA-RNA hybrids and a displaced DNA single strand (ssDNA), fulfill certain positive regulatory roles but are also a source of genomic instability. One key cellular mechanism to prevent R-loop accumulation centers on the conserved THO/TREX complex, an RNA-binding factor involved in transcription elongation and RNA export that contributes to messenger ribonucleoprotein (mRNP) assembly, but whose precise function is still unclear. To understand how THO restrains harmful R-loops, we searched for new THO-interacting factors...
October 26, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29072160/defining-the-location-of-promoter-associated-r-loops-at-near-nucleotide-resolution-using-bisdrip-seq
#16
Jason G Dumelie, Samie R Jaffrey
R-loops are features of chromatin consisting of a strand of DNA hybridized to RNA, as well as the expelled complementary DNA strand. R-loops are enriched at promoters where they have recently been shown to have important roles in modifying gene expression. However, the location of promoter-associated R-loops and the genomic domains they perturb to modify gene expression remain unclear. To resolve this issue, we developed a bisulfite-based approach, bisDRIP-seq, to map R-loops across the genome at near-nucleotide resolution in MCF-7 cells...
October 26, 2017: ELife
https://www.readbyqxmd.com/read/29061988/aquarius-is-required-for-proper-ctip-expression-and-homologous-recombination-repair
#17
Ryo Sakasai, Mayu Isono, Mitsuo Wakasugi, Mitsumasa Hashimoto, Yumi Sunatani, Tadashi Matsui, Atsushi Shibata, Tsukasa Matsunaga, Kuniyoshi Iwabuchi
Accumulating evidence indicates that transcription is closely related to DNA damage formation and that the loss of RNA biogenesis factors causes genome instability. However, whether such factors are involved in DNA damage responses remains unclear. We focus here on the RNA helicase Aquarius (AQR), a known R-loop processing factor, and show that its depletion in human cells results in the accumulation of DNA damage during S phase, mediated by R-loop formation. We investigated the involvement of Aquarius in DNA damage responses and found that AQR knockdown decreased DNA damage-induced foci formation of Rad51 and replication protein A, suggesting that Aquarius contributes to homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs)...
October 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29042409/recq-like-helicases-sgs1-and-blm-regulate-r-loop-associated-genome-instability
#18
Emily Yun-Chia Chang, Carolina A Novoa, Maria J Aristizabal, Yan Coulombe, Romulo Segovia, Richa Chaturvedi, Yaoqing Shen, Christelle Keong, Annie S Tam, Steven J M Jones, Jean-Yves Masson, Michael S Kobor, Peter C Stirling
Sgs1, the orthologue of human Bloom's syndrome helicase BLM, is a yeast DNA helicase functioning in DNA replication and repair. We show that SGS1 loss increases R-loop accumulation and sensitizes cells to transcription-replication collisions. Yeast lacking SGS1 accumulate R-loops and γ-H2A at sites of Sgs1 binding, replication pausing regions, and long genes. The mutation signature of sgs1Δ reveals copy number changes flanked by repetitive regions with high R-loop-forming potential. Analysis of BLM in Bloom's syndrome fibroblasts or by depletion of BLM from human cancer cells confirms a role for Sgs1/BLM in suppressing R-loop-associated genome instability across species...
October 17, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29038346/atr-is-a-therapeutic-target-in-synovial-sarcoma
#19
Samuel E Jones, Emmy D G Fleuren, Jessica Frankum, Asha Konde, Chris T Williamson, Dragomir B Krastev, Helen N Pemberton, James Campbell, Aditi Gulati, Richard Elliott, Malini Menon, Joanna L Selfe, Rachel Brough, Stephen J Pettitt, Wojciech Niedzwiedz, Winette T A van der Graaf, Janet Shipley, Alan Ashworth, Christopher J Lord
Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterised by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells to those in >130 non-SS tumour cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR...
October 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/29035497/conformational-dynamics-of-dna-binding-and-cas3-recruitment-by-the-crispr-rna-guide-cascade-complex
#20
Paul B G van Erp, Angela Patterson, Ravi Kant, Luke Berry, Sarah M Golden, Brittney L Forsman, Joshua Carter, Ryan N Jackson, Brian Bothner, Blake Wiedenheft
Bacteria and archaea rely on CRISPR (clustered regularly interspaced short palindromic repeats) RNA-guided adaptive immune systems for sequence specific elimination of foreign nucleic acids. In Escherichia coli, short CRISPR-derived RNAs (crRNAs) assemble with Cas (CRISPR-associated) proteins into a 405-kilodalton multi-subunit surveillance complex called Cascade (CRISPR-associated complex for antiviral defense). Cascade binds foreign DNA complementary to the crRNA guide and recruits Cas3, a trans-acting nuclease-helicase required for target degradation...
October 16, 2017: ACS Chemical Biology
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