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https://www.readbyqxmd.com/read/28942351/sphingosine-1-phosphate-and-cancer
#1
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
#2
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
#3
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
#4
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...
August 23, 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
#5
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 G-quadruplex, the constitutional superhelicity determines the potential and range of the formation of G-quadruplex by constraining the propagation of the negative supercoiling...
August 28, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28821455/rnase-hii-saves-rnha-mutant-escherichia-coli-from-r-loop-associated-chromosomal-fragmentation
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
Shankar Parajuli, Daniel C Teasley, 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. Although 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...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28714954/c9orf72-expansion-disrupts-atm-mediated-chromosomal-break-repair
#17
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...
September 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
#18
Dana Hodroj, Kamar Serhal, Domenico Maiorano
The DEAD-box Helicase 19 (Ddx19) gene codes for an RNA helicase involved in both mRNA (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
#19
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
#20
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
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