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https://www.readbyqxmd.com/read/29145633/the-initiation-propagation-and-dynamics-of-crispr-spycas9-r-loop-complex
#1
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
#2
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
#3
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...
October 31, 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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28977995/distinct-distributions-of-genomic-features-of-the-5-and-3-partners-of-coding-somatic-cancer-gene-fusions-arising-mechanisms-and-functional-implications
#11
Yongzhong Zhao, Won-Min Song, Fan Zhang, Ming-Ming Zhou, Weijia Zhang, Martin J Walsh, Bin Zhang
The genomic features and arising mechanisms of coding cancer somatic gene fusions (CSGFs) largely remain elusive. In this study, we show the gene origin stratification pattern of CSGF partners that fusion partners in human cancers are significantly enriched for genes with the gene age ofEuteleostomes and with the gene family age of Bilateria. GC skew (a measurement of G, C nucleotide content bias, (G-C)/(G+C)) is a useful measurement to indicate the DNA leading strand, lagging strand, replication origin, and replication terminal and DNA-RNA R-loop formation...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28977560/dynamic-nucleoplasmic-and-nucleolar-localization-of-mammalian-rnase-h1-in-response-to-rnap-i-transcriptional-r-loops
#12
Wen Shen, Hong Sun, Cheryl L De Hoyos, Jeffrey K Bailey, Xue-Hai Liang, Stanley T Crooke
An R-loop is a DNA:RNA hybrid formed during transcription when a DNA duplex is invaded by a nascent RNA transcript. R-loops accumulate in nucleoli during RNA polymerase I (RNAP I) transcription. Here, we report that mammalian RNase H1 enriches in nucleoli and co-localizes with R-loops in cultured human cells. Co-migration of RNase H1 and R-loops from nucleoli to perinucleolar ring structures was observed upon inhibition of RNAP I transcription. Treatment with camptothecin which transiently stabilized nucleolar R-loops recruited RNase H1 to the nucleoli...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28973905/physical-proximity-of-chromatin-to-nuclear-pores-prevents-harmful-r-loop-accumulation-contributing-to-maintain-genome-stability
#13
Francisco García-Benítez, Hélène Gaillard, Andrés Aguilera
During transcription, the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, constituting in this case a source of genomic instability. To understand the mechanism by which eukaryotic cells prevent harmful R loops, we used human activation-induced cytidine deaminase (AID) to identify genes preventing R loops. A screening of 400 Saccharomyces cerevisiae selected strains deleted in nuclear genes revealed that cells lacking the Mlp1/2 nuclear basket proteins show AID-dependent genomic instability and replication defects that were suppressed by RNase H1 overexpression...
October 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28970337/thrown-for-a-loop-how-rnaseh-and-dna-gyrases-limit-r-loops-and-maintain-genome-stability-in-chloroplasts
#14
Jennifer Mach
No abstract text is available yet for this article.
October 2, 2017: Plant Cell
https://www.readbyqxmd.com/read/28959243/rnase-h-as-gene-modifier-driver-of-evolution-and-antiviral-defense
#15
REVIEW
Karin Moelling, Felix Broecker, Giancarlo Russo, Shinichi Sunagawa
Retroviral infections are 'mini-symbiotic' events supplying recipient cells with sequences for viral replication, including the reverse transcriptase (RT) and ribonuclease H (RNase H). These proteins and other viral or cellular sequences can provide novel cellular functions including immune defense mechanisms. Their high error rate renders RT-RNases H drivers of evolutionary innovation. Integrated retroviruses and the related transposable elements (TEs) have existed for at least 150 million years, constitute up to 80% of eukaryotic genomes and are also present in prokaryotes...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28942351/sphingosine-1-phosphate-and-cancer
#16
REVIEW
Nigel J Pyne, Ashref El Buri, David R Adams, Susan Pyne
The bioactive lipid, sphingosine 1-phosphate (S1P) is produced by phosphorylation of sphingosine and this is catalysed by two sphingosine kinase isoforms (SK1 and SK2). Here we discuss structural functional aspects of SK1 (which is a dimeric quaternary enzyme) that relate to coordinated coupling of membrane association with phosphorylation of Ser225 in the 'so-called' R-loop, catalytic activity and protein-protein interactions (e.g. TRAF2, PP2A and Gq). S1P formed by SK1 at the plasma-membrane is released from cells via S1P transporters to act on S1P receptors to promote tumorigenesis...
September 15, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28939594/rnase-h1-cooperates-with-dna-gyrases-to-restrict-r-loops-and-maintain-genome-integrity-in-arabidopsis-chloroplasts
#17
Zhuo Yang, Quancan Hou, Lingling Cheng, Wei Xu, Yantao Hong, Shuai Li, Qianwen Sun
Maintaining organellar genome integrity is essential for eukaryotic cells, and many factors can threaten genome integrity. R-loops are DNA:RNA duplexes produced during transcription, with the non-templated DNA forming a single-stranded region. R-loops function in the regulation of transcription, DNA replication, and DNA repair, but can also be susceptible to lesions that form double-stranded breaks and thus induce genome instability. From investigating the function of a plant chloroplast localized R-loop removing enzyme AtRNH1C, we have found that it is responsible for plastid R-loop homeostasis, chloroplast genome instability and development...
September 22, 2017: Plant Cell
https://www.readbyqxmd.com/read/28923949/cytosine-deamination-and-base-excision-repair-cause-r-loop-induced-cag-repeat-fragility-and-instability-in-saccharomyces-cerevisiae
#18
Xiaofeng A Su, Catherine H Freudenreich
CAG/CTG repeats are structure-forming repetitive DNA sequences, and expansion beyond a threshold of ∼35 CAG repeats is the cause of several human diseases. Expanded CAG repeats are prone to breakage, and repair of the breaks can cause repeat contractions and expansions. In this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast chromosome. R-loops were further elevated upon deletion of yeast RNaseH genes and caused repeat fragility. A significant increase in CAG repeat contractions was also observed, consistent with previous human cell studies...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28846868/transcription-coupled-repair-deficiency-protects-against-human-mutagenesis-and-carcinogenesis-personal-reflections-on-the-50th-anniversary-of-the-discovery-of-xeroderma-pigmentosum
#19
REVIEW
James E Cleaver
Xeroderma pigmentosum (XP) patients who lack the main damage recognition protein for global genome repair (GGR), XPC, have greatly increased skin cancer rates and elevated mutation frequencies originating from unrepaired ultraviolet photoproducts in the nontranscribed regions of the genome and in nontranscribed strands of expressed genes. But they show no increased mutations in transcribed strands. In contrast, cancer is absent from Cockayne syndrome (CS) patients that have defective transcription coupled repair (TCR) despite severe photosensitivity, CS patients remarkably show no elevation of UV induced mutagenesis implying that defective TCR may be protective against mutagenesis and carcinogenesis...
October 2017: DNA Repair
https://www.readbyqxmd.com/read/28846373/superhelicity-constrains-a-localized-and-r-loop-dependent-formation-of-g-quadruplexes-at-the-upstream-region-of-transcription
#20
Ke-Wei Zheng, Yi-de He, Hong-He Liu, Xin-Min Li, Yu-Hua Hao, Zheng Tan
Transcription induces formation of intramolecular G-quadruplex structures at the upstream region of a DNA duplex by an upward transmission of negative supercoiling through the DNA. Currently the regulation of such G-quadruplex formation remains unclear. Using plasmid as a model, we demonstrate that while it is the dynamic negative supercoiling generated by a moving RNA polymerase that triggers a formation of a G-quadruplex, the constitutional superhelicity determines the potential and range of the formation of a G-quadruplex by constraining the propagation of the negative supercoiling...
September 11, 2017: ACS Chemical Biology
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