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"R-loops"

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https://www.readbyqxmd.com/read/29042409/recq-like-helicases-sgs1-and-blm-regulate-r-loop-associated-genome-instability
#1
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
#2
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
#3
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
#4
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
#5
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...
August 9, 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
#6
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...
September 25, 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
#7
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
#8
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
#9
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
#10
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
#11
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...
September 18, 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
#12
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
#13
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
https://www.readbyqxmd.com/read/28821455/rnase-hii-saves-rnha-mutant-escherichia-coli-from-r-loop-associated-chromosomal-fragmentation
#14
Elena A Kouzminova, Farid F Kadyrov, Andrei Kuzminov
The rnhAB mutant Escherichia coli, deficient in two RNase H enzymes that remove both R-loops and incorporated ribonucleotides (rNs) from DNA, grow slowly, suggesting accumulation of rN-containing DNA lesions (R-lesions). We report that the rnhAB mutants have reduced viability, form filaments with abnormal nucleoids, induce SOS, and fragment their chromosome, revealing replication and/or segregation stress. R-loops are known to interfere with replication forks, and sensitivity of the double rnhAB mutants to translation inhibition points to R-loops as precursors for R-lesions...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28819201/linker-histone-h1-prevents-r-loop-accumulation-and-genome-instability-in-heterochromatin
#15
Aleix Bayona-Feliu, Anna Casas-Lamesa, Oscar Reina, Jordi Bernués, Fernando Azorín
Linker histone H1 is an important structural component of chromatin that stabilizes the nucleosome and compacts the nucleofilament into higher-order structures. The biology of histone H1 remains, however, poorly understood. Here we show that Drosophila histone H1 (dH1) prevents genome instability as indicated by the increased γH2Av (H2AvS137P) content and the high incidence of DNA breaks and sister-chromatid exchanges observed in dH1-depleted cells. Increased γH2Av occurs preferentially at heterochromatic elements, which are upregulated upon dH1 depletion, and is due to the abnormal accumulation of DNA:RNA hybrids (R-loops)...
August 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28811374/recruitment-of-crispr-cas-systems-by-tn7-like-transposons
#16
Joseph E Peters, Kira S Makarova, Sergey Shmakov, Eugene V Koonin
A survey of bacterial and archaeal genomes shows that many Tn7-like transposons contain minimal type I-F CRISPR-Cas systems that consist of fused cas8f and cas5f, cas7f, and cas6f genes and a short CRISPR array. Several small groups of Tn7-like transposons encompass similarly truncated type I-B CRISPR-Cas. This minimal gene complement of the transposon-associated CRISPR-Cas systems implies that they are competent for pre-CRISPR RNA (precrRNA) processing yielding mature crRNAs and target binding but not target cleavage that is required for interference...
August 29, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28802046/replication-transcription-conflicts-generate-r-loops-that-orchestrate-bacterial-stress-survival-and-pathogenesis
#17
Kevin S Lang, Ashley N Hall, Christopher N Merrikh, Mark Ragheb, Hannah Tabakh, Alex J Pollock, Joshua J Woodward, Julia E Dreifus, Houra Merrikh
Replication-transcription collisions shape genomes, influence evolution, and promote genetic diseases. Although unclear why, head-on transcription (lagging strand genes) is especially disruptive to replication and promotes genomic instability. Here, we find that head-on collisions promote R-loop formation in Bacillus subtilis. We show that pervasive R-loop formation at head-on collision regions completely blocks replication, elevates mutagenesis, and inhibits gene expression. Accordingly, the activity of the R-loop processing enzyme RNase HIII at collision regions is crucial for stress survival in B...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802045/transcription-replication-conflict-orientation-modulates-r-loop-levels-and-activates-distinct-dna-damage-responses
#18
Stephan Hamperl, Michael J Bocek, Joshua C Saldivar, Tomek Swigut, Karlene A Cimprich
Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promoting their formation in the head-on (HO) orientation...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802036/transcription-replication-conflicts-orientation-matters
#19
COMMENT
Yea-Lih Lin, Philippe Pasero
Interference between DNA replication and transcription represents a major source of genomic instability. In this issue of Cell, Lang et al. and Hamperl et al. show that head-on collisions, but not codirectional collisions, impede fork progression in bacteria and in human cells by promoting the formation of RNA-DNA hybrids known as R-loops.
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28790157/sirt7-and-the-dead-box-helicase-ddx21-cooperate-to-resolve-genomic-r-loops-and-safeguard-genome-stability
#20
Chenlin Song, Agnes Hotz-Wagenblatt, Renate Voit, Ingrid Grummt
R loops are three-stranded nucleic acid structures consisting of an RNA:DNA heteroduplex and a "looped-out" nontemplate strand. As aberrant formation and persistence of R loops block transcription elongation and cause DNA damage, mechanisms that resolve R loops are essential for genome stability. Here we show that the DEAD (Asp-Glu-Ala-Asp)-box RNA helicase DDX21 efficiently unwinds R loops and that depletion of DDX21 leads to accumulation of cellular R loops and DNA damage. Significantly, the activity of DDX21 is regulated by acetylation...
August 8, 2017: Genes & Development
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