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"R-loops"

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https://www.readbyqxmd.com/read/28821455/rnase-hii-saves-rnha-mutant-escherichia-coli-from-r-loop-associated-chromosomal-fragmentation
#1
Elena A Kouzminova, Farid F Kadyrov, Andrei Kuzminov
The rnhAB mutant E. 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...
August 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28819201/linker-histone-h1-prevents-r-loop-accumulation-and-genome-instability-in-heterochromatin
#2
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
#3
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 15, 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
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28781236/structural-variation-of-type-i-f-crispr-rna-guided-dna-surveillance
#8
Patrick Pausch, Hanna Müller-Esparza, Daniel Gleditzsch, Florian Altegoer, Lennart Randau, Gert Bange
CRISPR-Cas systems are prokaryotic immune systems against invading nucleic acids. Type I CRISPR-Cas systems employ highly diverse, multi-subunit surveillance Cascade complexes that facilitate duplex formation between crRNA and complementary target DNA for R-loop formation, retention, and DNA degradation by the subsequently recruited nuclease Cas3. Typically, the large subunit recognizes bona fide targets through the PAM (protospacer adjacent motif), and the small subunit guides the non-target DNA strand. Here, we present the Apo- and target-DNA-bound structures of the I-Fv (type I-F variant) Cascade lacking the small and large subunits...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28760773/alternative-lengthening-of-telomeres-mediated-by-mitotic-dna-synthesis-engages-break-induced-replication-processes
#9
Jaewon Min, Woodring E Wright, Jerry W Shay
Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase positive cells and their hTERC knockout derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in S...
July 31, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28757210/introns-protect-eukaryotic-genomes-from-transcription-associated-genetic-instability
#10
Amandine Bonnet, Ana R Grosso, Abdessamad Elkaoutari, Emeline Coleno, Adrien Presle, Sreerama C Sridhara, Guilhem Janbon, Vincent Géli, Sérgio F de Almeida, Benoit Palancade
Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28717002/human-ribonuclease-h1-resolves-r-loops-and-thereby-enables-progression-of-the-dna-replication-fork
#11
Shankar Parajuli, Daniel C Tealsey, Bhavna Murali, Jessica Jackson, Alessandro Vindigni, Sheila A Stewart
Faithful DNA replication is essential for genome stability. To ensure accurate replication, numerous complex and redundant replication and repair mechanisms function in tandem with the core replication proteins to ensure DNA replication continues even when replication challenges are present that could impede progression of the replication fork. A unique topological challenge to the replication machinery is posed by RNA:DNA hybrids, commonly referred to as R-loops. While R-loops play important roles in gene expression and recombination at immunoglobulin sites, their persistence is thought to interfere with DNA replication by slowing or impeding replication fork progression...
July 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28714954/c9orf72-expansion-disrupts-atm-mediated-chromosomal-break-repair
#12
Callum Walker, Saul Herranz-Martin, Evangelia Karyka, Chunyan Liao, Katherine Lewis, Waheba Elsayed, Vera Lukashchuk, Shih-Chieh Chiang, Swagat Ray, Padraig J Mulcahy, Mateusz Jurga, Ioannis Tsagakis, Tommaso Iannitti, Jayanth Chandran, Ian Coldicott, Kurt J De Vos, Mohamed K Hassan, Adrian Higginbottom, Pamela J Shaw, Guillaume M Hautbergue, Mimoun Azzouz, Sherif F El-Khamisy
Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks...
July 17, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28696814/ddx19-links-mrna-nuclear-export-with-progression-of-transcription-and-replication-and-suppresses-genomic-instability-upon-dna-damage-in-proliferating-cells
#13
Dana Hodroj, Kamar Serhal, Domenico Maiorano
The DEAD-box Helicase 19 (Ddx19) gene codes for an RNA helicase involved in both messenger RNA (mRNA) export from the nucleus into the cytoplasm and in mRNA translation. In unperturbed cells, Ddx19 localizes in the cytoplasm and at the cytoplasmic face of the nuclear pore. Here we review recent findings related to an additional Ddx19 function in the nucleus in resolving RNA:DNA hybrids (R-loops) generated during collision between transcription and replication, and upon DNA damage. Activation of a DNA damage response pathway dependent upon the ATR kinase, a major regulator of replication fork progression, stimulates translocation of the Ddx19 protein from the cytoplasm into the nucleus...
July 11, 2017: Nucleus
https://www.readbyqxmd.com/read/28678773/erratum-structure-of-the-cpf1-endonuclease-r-loop-complex-after-target-dna-cleavage
#14
Stefano Stella, Pablo Alcón, Guillermo Montoya
This corrects the article DOI: 10.1038/nature22398.
July 27, 2017: Nature
https://www.readbyqxmd.com/read/28673893/from-intronization-to-intron-loss-how-the-interplay-between-mrna-associated-processes-can-shape-the-architecture-and-the-expression-of-eukaryotic-genes
#15
Francesco Catania
Transcription-coupled processes such as capping, splicing, and cleavage/polyadenylation participate in the journey from genes to proteins. Although they are traditionally thought to serve only as steps in the generation of mature mRNAs, a synthesis of available data indicates that these processes could also act as a driving force for the evolution of eukaryotic genes. A theoretical framework for how mRNA-associated processes may shape gene structure and expression has recently been proposed. Factors that promote splicing and cleavage/polyadenylation in this framework compete for access to overlapping or neighboring signals throughout the transcription cycle...
June 30, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28666126/telomere-length-determines-terra-and-r-loop-regulation-through-the-cell-cycle
#16
Marco Graf, Diego Bonetti, Arianna Lockhart, Kamar Serhal, Vanessa Kellner, André Maicher, Pascale Jolivet, Maria Teresa Teixeira, Brian Luke
Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28666122/structure-basis-for-directional-r-loop-formation-and-substrate-handover-mechanisms-in-type-i-crispr-cas-system
#17
Yibei Xiao, Min Luo, Robert P Hayes, Jonathan Kim, Sherwin Ng, Fang Ding, Maofu Liao, Ailong Ke
Type I CRISPR systems feature a sequential dsDNA target searching and degradation process, by crRNA-displaying Cascade and nuclease-helicase fusion enzyme Cas3, respectively. Here we present two cryo-EM snapshots of the Thermobifida fusca type I-E Cascade: (1) unwinding 11 bp of dsDNA at the seed-sequence region to scout for sequence complementarity, and (2) further unwinding of the entire protospacer to form a full R-loop. These structures provide the much-needed temporal and spatial resolution to resolve key mechanistic steps leading to Cas3 recruitment...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28658920/management-of-an-unusual-ectopic-eruption-of-maxillary-canine
#18
Kaladhar Reddy Aileni, Madhukar Reddy Rachala, Chintakunta Reddy Prathima, Pitalla Kumar Naveen, Donthula Soujanya
Transposition of teeth is a rare condition, with a prevalence of 0.3-0.4% in general population. They are more commonly observed in females, and may occur unilaterally/bilaterally with greater frequency of left side occurrence in unilateral transposition cases. A 17-year-old female patient reported with the chief complaint of unaesthetic smile. On clinical examination the patient was diagnosed with Angle's class I malocclusion with an ectopically erupted maxillary left canine labial to the left central incisor with retained deciduous canine...
May 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28653981/the-role-of-replication-associated-repair-factors-on-r-loops
#19
REVIEW
Vaibhav Bhatia, Emilia Herrera-Moyano, Andrés Aguilera, Belén Gómez-González
The nascent RNA can reinvade the DNA double helix to form a structure termed the R-loop, where a single-stranded DNA (ssDNA) is accompanied by a DNA-RNA hybrid. Unresolved R-loops can impede transcription and replication processes and lead to genomic instability by a mechanism still not fully understood. In this sense, a connection between R-loops and certain chromatin markers has been reported that might play a key role in R-loop homeostasis and genome instability. To counteract the potential harmful effect of R-loops, different conserved messenger ribonucleoprotein (mRNP) biogenesis and nuclear export factors prevent R-loop formation, while ubiquitously-expressed specific ribonucleases and DNA-RNA helicases resolve DNA-RNA hybrids...
June 27, 2017: Genes
https://www.readbyqxmd.com/read/28649985/attenuation-of-rna-polymerase-ii-pausing-mitigates-brca1-associated-r-loop-accumulation-and-tumorigenesis
#20
Xiaowen Zhang, Huai-Chin Chiang, Yao Wang, Chi Zhang, Sabrina Smith, Xiayan Zhao, Sreejith J Nair, Joel Michalek, Ismail Jatoi, Meeghan Lautner, Boyce Oliver, Howard Wang, Anna Petit, Teresa Soler, Joan Brunet, Francesca Mateo, Miguel Angel Pujana, Elizabeth Poggi, Krysta Chaldekas, Claudine Isaacs, Beth N Peshkin, Oscar Ochoa, Frederic Chedin, Constantine Theoharis, Lu-Zhe Sun, Tyler J Curiel, Richard Elledge, Victor X Jin, Yanfen Hu, Rong Li
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers...
June 26, 2017: Nature Communications
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