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https://www.readbyqxmd.com/read/30322030/the-emerging-role-of-dna-damage-in-the-pathogenesis-of-the-c9orf72-repeat-expansion-in-amyotrophic-lateral-sclerosis
#1
REVIEW
Anna Konopka, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 ( C9orf72 ) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats...
October 12, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/30304482/genome-wide-mapping-reveals-conserved-and-diverged-r-loop-activities-in-the-unusual-genetic-landscape-of-the-african-trypanosome-genome
#2
Emma Briggs, Graham Hamilton, Kathryn Crouch, Craig Lapsley, Richard McCulloch
R-loops are stable RNA-DNA hybrids that have been implicated in transcription initiation and termination, as well as in telomere maintenance, chromatin formation, and genome replication and instability. RNA Polymerase (Pol) II transcription in the protozoan parasite Trypanosoma brucei is highly unusual: virtually all genes are co-transcribed from multigene transcription units, with mRNAs generated by linked trans-splicing and polyadenylation, and transcription initiation sites display no conserved promoter motifs...
October 10, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/30301808/human-mitochondrial-degradosome-prevents-harmful-mitochondrial-r-loops-and-mitochondrial-genome-instability
#3
Sonia Silva, Lola P Camino, Andrés Aguilera
R loops are nucleic acid structures comprising an DNA-RNA hybrid and a displaced single-stranded DNA. These structures may occur transiently during transcription, playing essential biological functions. However, persistent R loops may become pathological as they are important drivers of genome instability and have been associated with human diseases. The mitochondrial degradosome is a functionally conserved complex from bacteria to human mitochondria. It is composed of the ATP-dependent RNA and DNA helicase SUV3 and the PNPase ribonuclease, playing a central role in mitochondrial RNA surveillance and degradation...
October 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/30297739/ros-induced-r-loops-trigger-a-transcription-coupled-but-brca1-2-independent-homologous-recombination-pathway-through-csb
#4
Yaqun Teng, Tribhuwan Yadav, Meihan Duan, Jun Tan, Yufei Xiang, Boya Gao, Jianquan Xu, Zhuobin Liang, Yang Liu, Satoshi Nakajima, Yi Shi, Arthur S Levine, Lee Zou, Li Lan
Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a transcribed locus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 to damage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and Cockayne Syndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain...
October 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/30266813/rad52-promotes-transcription-associated-homologous-recombination-repair
#5
(no author information available yet)
RAD52-mediated processing of R-loops initiates high-fidelity DNA repair in actively transcribed regions.
September 28, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/30262458/the-dead-box-protein-dbp2p-is-linked-to-non-coding-rnas-the-helicase-sen1p-and-r-loops
#6
Frank A Tedeschi, Sara C Cloutier, Elizabeth J Tran, Eckhard Jankowsky
The DEAD-box RNA helicase Dbp2p is highly conserved in eukaryotes and has been implicated in transcription, ribosome biogenesis, mRNP assembly, nuclear export, and lncRNA function. It is not understood how Dbp2p performs these seemingly unrelated biological roles. An important step towards addressing this question is the determination of cellular RNA binding sites of Dbp2p. Here, we identify transcriptome-wide RNA binding sites of Dbp2p from Saccharomyces cerevisiae using UV-crosslinking, denaturing tandem affinity purification, and Next Generation Sequencing...
September 27, 2018: RNA
https://www.readbyqxmd.com/read/30250139/crystal-structures-of-multicopper-oxidase-cueo-g304k-mutant-structural-basis-of-the-increased-laccase-activity
#7
Hanqian Wang, Xiaoqing Liu, Jintong Zhao, Qingxia Yue, Yuhua Yan, Zengqiang Gao, Yuhui Dong, Zhiyong Zhang, Yunliu Fan, Jian Tian, Ningfeng Wu, Yong Gong
The multicopper oxidase CueO is involved in copper homeostasis and copper (Cu) tolerance in Escherichia coli. The laccase activity of CueO G304K mutant is higher than wild-type CueO. To explain this increase in activity, we solved the crystal structure of G304K mutant at 1.49 Å. Compared with wild-type CueO, the G304K mutant showed dramatic conformational changes in methionine-rich helix and the relative regulatory loop (R-loop). We further solved the structure of Cu-soaked enzyme, and found that the addition of Cu ions induced further conformational changes in the R-loop and methionine-rich helix as a result of the new Cu-binding sites on the enzyme's surface...
September 24, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30245011/human-rad52-promotes-xpg-mediated-r-loop-processing-to-initiate-transcription-associated-homologous-recombination-repair
#8
Takaaki Yasuhara, Reona Kato, Yoshihiko Hagiwara, Bunsyo Shiotani, Motohiro Yamauchi, Shinichiro Nakada, Atsushi Shibata, Kiyoshi Miyagawa
Given that genomic DNA exerts its function by being transcribed, it is critical for the maintenance of homeostasis that DNA damage, such as double-strand breaks (DSBs), within transcriptionally active regions undergoes accurate repair. However, it remains unclear how this is achieved. Here, we describe a mechanism for transcription-associated homologous recombination repair (TA-HRR) in human cells. The process is initiated by R-loops formed upon DSB induction. We identify Rad52, which is recruited to the DSB site in a DNA-RNA-hybrid-dependent manner, as playing pivotal roles in promoting XPG-mediated R-loop processing and initiating subsequent repair by HRR...
October 4, 2018: Cell
https://www.readbyqxmd.com/read/30238851/investigation-of-selective-binding-of-inhibitors-to-ptp1b-and-tcptp-by-accelerated-molecular-dynamics-simulations
#9
Xi Chen, Qiang Gan, Changgen Feng, Xia Liu, Qian Zhang
Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator in insulin signaling pathways, is regarded as a potential target for the treatment of type II diabetes and obesity. However, the mechanism underlying the selectivity of PTP1B inhibitors against T-cell protein tyrosine phosphatase (TCPTP) remains controversial, which is due to the high similarity between PTP1B and TCPTP sequence and the fact that no ligand-protein complex of TCPTP has been established yet. Here, the accelerated molecular dynamics (aMD) method was used to investigate structural dynamics of PTP1B and TCPTP that are bound by two chemically similar inhibitors with distinct selectivity...
September 21, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/30222737/topoisomerases-i-and-iii-inhibit-r-loop-formation-to-prevent-unregulated-replication-in-the-chromosomal-ter-region-of-escherichia-coli
#10
Julien Brochu, Émilie Vlachos-Breton, Sarah Sutherland, Makisha Martel, Marc Drolet
Type 1A topoisomerases (topos) are the only ubiquitous topos. E. coli has two type 1A topos, topo I (topA) and topo III (topB). Topo I relaxes negative supercoiling in part to inhibit R-loop formation. To grow, topA mutants acquire compensatory mutations, base substitutions in gyrA or gyrB (gyrase) or amplifications of a DNA region including parC and parE (topo IV). topB mutants grow normally and topo III binds tightly to single-stranded DNA. What functions topo I and III share in vivo and how cells lacking these important enzymes can survive is unclear...
September 2018: PLoS Genetics
https://www.readbyqxmd.com/read/30190235/r-loop-generation-during-transcription-formation-processing-and-cellular-outcomes
#11
Boris P Belotserkovskii, Silvia Tornaletti, Alicia D D'Souza, Philip C Hanawalt
R-loops are structures consisting of an RNA-DNA duplex and an unpaired DNA strand. They can form during transcription upon nascent RNA "threadback" invasion into the DNA duplex to displace the non-template strand. Although R-loops occur naturally in all kingdoms of life and serve regulatory roles, they are often deleterious and can cause genomic instability. Of particular importance are the disastrous consequences when replication forks or transcription complexes collide with R-loops. The appropriate processing of R-loops is essential to avoid a number of human neurodegenerative and other clinical disorders...
August 25, 2018: DNA Repair
https://www.readbyqxmd.com/read/30108179/human-proteins-that-interact-with-rna-dna-hybrids
#12
Isabel X Wang, Christopher Grunseich, Jennifer Fox, Joshua Burdick, Zhengwei Zhu, Niema Ravazian, Markus Hafner, Vivian G Cheung
RNA/DNA hybrids form when RNA hybridizes with its template DNA generating a three-stranded structure known as the R-loop. Knowledge of how they form and resolve, as well as their functional roles, is limited. Here, by pull-down assays followed by mass spectrometry, we identified 803 proteins that bind to RNA/DNA hybrids. Because these proteins were identified using in vitro assays, we confirmed that they bind to R-loops in vivo. They include proteins that are involved in a variety of functions, including most steps of RNA processing...
September 2018: Genome Research
https://www.readbyqxmd.com/read/30096986/dna-replication-roadblocks-caused-by-cascade-interference-complexes-are-alleviated-by-recg-dna-repair-helicase
#13
Tom Killelea, Michelle Hawkins, Jamieson L Howard, Peter McGlynn, Edward L Bolt
Cascade complexes underpin E. coli CRISPR-Cas immunity systems by stimulating 'adaptation' reactions that update immunity and by initiating 'interference' reactions that destroy invader DNA. Recognition of invader DNA in Cascade catalysed R-loops provokes DNA capture and its subsequent integration into CRISPR loci by Cas1 and Cas2. DNA capture processes are unclear but may involve RecG helicase, which stimulates adaptation during its role responding to genome instability. We show that Cascade is a potential source of genome instability because it blocks DNA replication and that RecG helicase alleviates this by dissociating Cascade...
August 10, 2018: RNA Biology
https://www.readbyqxmd.com/read/30078724/kinetic-basis-for-dna-target-specificity-of-crispr-cas12a
#14
Isabel Strohkendl, Fatema A Saifuddin, James R Rybarski, Ilya J Finkelstein, Rick Russell
Class 2 CRISPR-Cas nucleases are programmable genome editing tools with promising applications in human health and disease. However, DNA cleavage at off-target sites that resemble the target sequence is a pervasive problem that remains poorly understood mechanistically. Here, we use quantitative kinetics to dissect the reaction steps of DNA targeting by Acidaminococcus sp Cas12a (also known as Cpf1). We show that Cas12a binds DNA tightly in two kinetically separable steps. Protospacer-adjacent motif (PAM) recognition is followed by rate-limiting R-loop propagation, leading to inevitable DNA cleavage of both strands...
September 6, 2018: Molecular Cell
https://www.readbyqxmd.com/read/30078723/genome-wide-map-of-r-loop-induced-damage-reveals-how-a-subset-of-r-loops-contributes-to-genomic-instability
#15
Lorenzo Costantino, Douglas Koshland
DNA-RNA hybrids associated with R-loops promote DNA damage and genomic instability. The capacity of hybrids at different genomic sites to cause DNA damage was not known, and the mechanisms leading from hybrid to damage were poorly understood. Here, we adopt a new strategy to map and characterize the sites of hybrid-induced damage genome-wide in budding yeast. We show that hybrid removal is essential for life because persistent hybrids cause irreparable DNA damage and cell death. We identify that a subset of hybrids is prone to cause damage, and the chromosomal context of hybrids dramatically impacts their ability to induce damage...
August 16, 2018: Molecular Cell
https://www.readbyqxmd.com/read/30060749/dna-topoisomerase-i-differentially-modulates-r-loops-across-the-human-genome
#16
Stefano G Manzo, Stella R Hartono, Lionel A Sanz, Jessica Marinello, Sara De Biasi, Andrea Cossarizza, Giovanni Capranico, Frederic Chedin
BACKGROUND: Co-transcriptional R-loops are abundant non-B DNA structures in mammalian genomes. DNA Topoisomerase I (Top1) is often thought to regulate R-loop formation owing to its ability to resolve both positive and negative supercoils. How Top1 regulates R-loop structures at a global level is unknown. RESULTS: Here, we perform high-resolution strand-specific R-loop mapping in human cells depleted for Top1 and find that Top1 depletion results in both R-loop gains and losses at thousands of transcribed loci, delineating two distinct gene classes...
July 30, 2018: Genome Biology
https://www.readbyqxmd.com/read/30054334/spliceosome-mutations-induce-r-loop-associated-sensitivity-to-atr-inhibition-in-myelodysplastic-syndromes
#17
Hai Dang Nguyen, Wan Yee Leong, Weiling Li, Pavankumar N G Reddy, Jack D Sullivan, Matthew J Walter, Lee Zou, Timothy A Graubert
Heterozygous somatic mutations in spliceosome genes ( U2AF1, SF3B1, ZRSR2 , or SRSF2 ) occur in >50% of patients with myelodysplastic syndrome (MDS). These mutations occur early in disease development, suggesting that they contribute to MDS pathogenesis and may represent a unique genetic vulnerability for targeted therapy. Here, we show that RNA splicing perturbation by expression of the U2AF1(S34F) mutant causes accumulation of R loops, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA, and elicits an ATR response...
September 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/30053183/toward-predictive-r-loop-computational-biology-genome-scale-prediction-of-r-loops-reveals-their-association-with-complex-promoter-structures-g-quadruplexes-and-transcriptionally-active-enhancers
#18
Vladimir A Kuznetsov, Vladyslav Bondarenko, Thidathip Wongsurawat, Surya P Yenamandra, Piroon Jenjaroenpun
No abstract text is available yet for this article.
September 6, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/30053106/the-pif1-signature-motif-of-pfh1-is-necessary-for-both-protein-displacement-and-helicase-unwinding-activities-but-is-dispensable-for-strand-annealing-activity
#19
Jani B Mohammad, Marcus Wallgren, Nasim Sabouri
Pfh1, the sole member of the Pif1 helicases in Schizosaccharomyces pombe, is multifunctional and essential for maintenance of both the nuclear and mitochondrial genomes. However, we lack mechanistic insights into the functions of Pfh1 and its different motifs. This paper is specifically concerned with the importance of the Pif1 signature motif (SM), a 23 amino acids motif unique to Pif1 helicases, because a single amino acid substitution in this motif is associated with increased risk of breast cancer in humans and inviability in S...
September 19, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/30047099/r-loops-in-motor-neuron-diseases
#20
REVIEW
Martina G L Perego, Michela Taiana, Nereo Bresolin, Giacomo P Comi, Stefania Corti
R loops are transient three-stranded nucleic acid structures that form physiologically during transcription when a nascent RNA transcript hybridizes with the DNA template strand, leaving a single strand of displaced nontemplate DNA. However, aberrant persistence of R-loops can cause DNA damage by inducing genomic instability. Indeed, evidence has emerged that R-loops might represent a key element in the pathogenesis of human diseases, including cancer, neurodegeneration, and motor neuron disorders. Mutations in genes directly involved in R-loop biology, such as SETX (senataxin), or unstable DNA expansion eliciting R-loop generation, such as C9ORF72 HRE, can cause DNA damage and ultimately result in motor neuron cell death...
July 25, 2018: Molecular Neurobiology
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