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https://www.readbyqxmd.com/read/28729824/mouse-models-of-c9orf72-hexanucleotide-repeat-expansion-in-amyotrophic-lateral-sclerosis-frontotemporal-dementia
#1
REVIEW
Ranjan Batra, Chris W Lee
The presence of hexanucleotide repeat expansion (HRE) in the first intron of the human C9orf72 gene is the most common genetic cause underlying both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies aimed at elucidating the pathogenic mechanisms associated of C9orf72 FTD and ALS (C9FTD/ALS) have focused on the hypothesis of RNA and protein toxic gain-of-function models, including formation of nuclear RNA foci containing GGGGCC (G4C2) HRE, inclusions containing dipeptide repeat proteins through a non-canonical repeat associated non-ATG (RAN) translation mechanism, and on loss-of-function of the C9orf72 protein...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28728523/structural-insights-into-the-binding-of-small-ligand-molecules-to-a-g-quadruplex-dna-located-in-the-hiv-1-promoter
#2
Petar M Mitrasinovic
Targeting guanine (G)-rich DNA sequences, folded into non-canonical G-quadruplex (G4) structures, by small ligand molecules is a promising strategy for gene therapy of various diseases. There is experimental proposal that, among eight studied ligands, nitidine chloride - NC and a benzo phenanthridine derivative - BPD have the highest binding affinities for such a sequence (5'-T(1)G(2)G(3)C(4)C(5)T(6)G(7)G(8)G(9)C(10)G(11)G(12)G(13)A(14)C(15)T(16)G(17)G(18)G(19)-3') in the HIV-1 promoter, indicating that an anti-HIV-1 prodrug may regulate the expression of the promoter...
July 20, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28719624/sequence-specific-dna-binding-by-myc-max-to-low-affinity-non-e-box-motifs
#3
Michael Allevato, Eugene Bolotin, Mark Grossman, Daniel Mane-Padros, Frances M Sladek, Ernest Martinez
The MYC oncoprotein regulates transcription of a large fraction of the genome as an obligatory heterodimer with the transcription factor MAX. The MYC:MAX heterodimer and MAX:MAX homodimer (hereafter MYC/MAX) bind Enhancer box (E-box) DNA elements (CANNTG) and have the greatest affinity for the canonical MYC E-box (CME) CACGTG. However, MYC:MAX also recognizes E-box variants and was reported to bind DNA in a "non-specific" fashion in vitro and in vivo. Here, in order to identify potential additional non-canonical binding sites for MYC/MAX, we employed high throughput in vitro protein-binding microarrays, along with electrophoretic mobility-shift assays and bioinformatic analyses of MYC-bound genomic loci in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28717872/stress-induced-changes-in-mirna-biogenesis-and-functioning
#4
REVIEW
Marta Olejniczak, Anna Kotowska-Zimmer, Wlodzimierz Krzyzosiak
MicroRNAs (miRNAs) are small, noncoding RNAs that play key roles in the regulation of cellular homeostasis in eukaryotic organisms. There is emerging evidence that some of these processes are influenced by various forms of cellular stresses, including DNA damage, pathogen invasion or chronic stress associated with diseases. Many reports over the last decade demonstrate examples of stress-induced miRNA deregulation at the level of transcription, processing, subcellular localization and functioning. Moreover, core miRNA biogenesis proteins and their interactions with partners can be selectively regulated in response to stress signaling...
July 17, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28714476/modulation-of-nongenomic-activation-of-pi3k-signalling-by-tetramerization-of-n-terminally-cleaved-rxr%C3%AE
#5
Liqun Chen, Alexander E Aleshin, Gulimiran Alitongbieke, Yuqi Zhou, Xindao Zhang, Xiaohong Ye, Mengjie Hu, Gaoang Ren, Ziwen Chen, Yue Ma, Duo Zhang, Shuai Liu, Weiwei Gao, Lijun Cai, Lingjuan Wu, Zhiping Zeng, Fuquan Jiang, Jie Liu, Hu Zhou, Gregory Cadwell, Robert C Liddington, Ying Su, Xiao-Kun Zhang
Retinoid X receptor-alpha (RXRα) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRα tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28687761/inactivation-of-pol-%C3%AE-and-c-nhej-eliminates-off-target-integration-of-exogenous-dna
#6
Alex N Zelensky, Joost Schimmel, Hanneke Kool, Roland Kanaar, Marcel Tijsterman
Off-target or random integration of exogenous DNA hampers precise genomic engineering and presents a safety risk in clinical gene therapy strategies. Genetic definition of random integration has been lacking for decades. Here, we show that the A-family DNA polymerase θ (Pol θ) promotes random integration, while canonical non-homologous DNA end joining plays a secondary role; cells double deficient for polymerase θ and canonical non-homologous DNA end joining are devoid of any integration events, demonstrating that these two mechanisms define random integration...
July 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28686609/self-consistent-theory-of-transcriptional-control-in-complex-regulatory-architectures
#7
Jasper Landman, Robert C Brewster, Franz M Weinert, Rob Phillips, Willem K Kegel
Individual regulatory proteins are typically charged with the simultaneous regulation of a battery of different genes. As a result, when one of these proteins is limiting, competitive effects have a significant impact on the transcriptional response of the regulated genes. Here we present a general framework for the analysis of any generic regulatory architecture that accounts for the competitive effects of the regulatory environment by isolating these effects into an effective concentration parameter. These predictions are formulated using the grand-canonical ensemble of statistical mechanics and the fold-change in gene expression is predicted as a function of the number of transcription factors, the strength of interactions between the transcription factors and their DNA binding sites, and the effective concentration of the transcription factor...
2017: PloS One
https://www.readbyqxmd.com/read/28657760/effect-of-monovalent-ion-parameters-on-molecular-dynamics-simulations-of-g-quadruplexes
#8
Marek Havrila, Petr Stadlbauer, Barira Islam, Michal Otyepka, Jiri Sponer
G-quadruplexes (GQs) are key non-canonical DNA and RNA architectures stabilized by desolvated monovalent cations present in their central channels. We analyze extended atomistic molecular dynamics simulations (~ 580 µs in total) of GQs with eleven monovalent cation parametrizations, assessing GQ overall structural stability, dynamics of internal cations and distortions of the G-tetrad geometries. Majority of simulations were executed with the SPC/E water model, however, test simulations with TIP3P and OPC water models are also reported...
June 28, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28654813/conformational-flexibility-and-base-pairing-tendency-of-the-tobacco-carcinogen-o6-4-oxo-4-3-pyridyl-butyl-guanine
#9
Katie A Wilson, Kariann G Szemethy, Stacey D Wetmore
The present work uses DFT calculations to characterize the conformational and hydrogen-bonding properties of O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G), a DNA adduct caused by tobacco. POB-G is found to adopt many isoenergetic conformations that allow for discrete interactions between the bulky moiety and the adducted G and/or pairing base. The calculated structure and stability of the hydrogen-bonded pairs between the Watson-Crick or Hoogsteen face of POB-G and the canonical DNA nucleobases fully rationalize the previously reported mutational spectra...
June 10, 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/28652006/3d-nus-a-web-server-for-automated-modeling-and-visualization-of-non-canonical-3-dimensional-nucleic-acid-structures
#10
L Ponoop Prasad Patro, Abhishek Kumar, Narendar Kolimi, Thenmalarchelvi Rathinavelan
The inherent conformational flexibility of nucleic acids facilitates the formation of a range of conformations such as duplex, triplex, quadruplex, etc. that play crucial roles in biological processes. Elucidation of the influence of non-canonical base pair mismatches on DNA/RNA structures at different sequence contexts to understand the mismatch repair, misregulation of alternative splicing mechanisms and the sequence-dependent effect of RNA-DNA hybrid in relevance to antisense strategy demand their three-dimensional structural information...
June 23, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28634160/high-throughput-characterization-of-cascade-type-i-e-crispr-guide-efficacy-reveals-unexpected-pam-diversity-and-target-sequence-preferences
#11
Becky Xu Hua Fu, Michael Wainberg, Anshul Kundaje, Andrew Z Fire
Interactions between Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) RNAs and CRISPR-associated (Cas) proteins form an RNA-guided adaptive immune system in prokaryotes. The adaptive immune system utilizes segments of the genetic material of invasive foreign elements in the CRISPR locus. The loci are transcribed and processed to produce small CRISPR RNAs (crRNAs), with degradation of invading genetic material directed by a combination of complementarity between RNA and DNA and in some cases recognition of adjacent motifs called PAMs (Protospacer Adjacent Motifs)...
June 20, 2017: Genetics
https://www.readbyqxmd.com/read/28631178/recent-insights-into-the-molecular-basis-of-fanconi-anemia-genes-modifiers-and-drivers
#12
REVIEW
Ronald S Cheung, Toshiyasu Taniguchi
Fanconi anemia (FA), the most common form of inherited bone marrow failure, predisposes to leukemia and solid tumors. FA is caused by the genetic disruption of a cellular pathway that repairs DNA interstrand crosslinks. The impaired function of this pathway, and the genetic instability that results, is considered the main pathogenic mechanism behind this disease. The identification of breast cancer susceptibility genes (for example, BRCA1/FANCS and BRCA2/FANCD1) as being major players in the FA pathway has led to a surge in molecular studies, resulting in the concept of the FA-BRCA pathway...
June 19, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28629776/unveiling-the-non-repair-face-of-the-base-excision-repair-pathway-in-rna-processing-a-missing-link-between-dna-repair-and-gene-expression
#13
REVIEW
Giulia Antoniali, Matilde Clarissa Malfatti, Gianluca Tell
The Base Excision Repair (BER) pathway, initially studied as a mere DNA repair pathway, has been later found to be implicated in the expression of cancer related genes in human. For several years, this intricate involvement in apparently different processes represented a mystery, which we now are starting to unveil. The BER handles simple alkylation and oxidative lesions arising from both endogenous and exogenous sources, including cancer therapy agents. Surprisingly, BER pathway involvement in transcriptional regulation, immunoglobulin variability and switch recombination, RNA metabolism and nucleolar function is astonishingly consolidating...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28625978/the-alkylating-chemotherapeutic-temozolomide-induces-metabolic-stress-in-idh1-mutant-cancers-and-potentiates-nad-depletion-mediated-cytotoxicity
#14
Kensuke Tateishi, Fumi Higuchi, Julie Miller, Mara V A Koerner, Nina Lelic, Ganesh M Shankar, Shota Tanaka, David E Fisher, Tracy Batchelor, A John Iafrate, Hiroaki Wakimoto, Andrew S Chi, Daniel P Cahill
IDH1-mutant gliomas are dependent upon the canonical coenzyme nicotinamide adenine dinucleotide (NAD+) for survival. It is known that Poly(ADP-ribose) polymerase (PARP) activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide (TMZ) could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of TMZ on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to TMZ, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis...
June 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28622525/atm-atr-and-dna-pk-the-trinity-at-the-heart-of-the-dna-damage-response
#15
REVIEW
Andrew N Blackford, Stephen P Jackson
In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health...
June 15, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28605461/determining-the-folding-and-binding-free-energy-of-dna-based-nanodevices-and-nanoswitches-using-urea-titration-curves
#16
Andrea Idili, Francesco Ricci, Alexis Vallée-Bélisle
DNA nanotechnology takes advantage of the predictability of DNA interactions to build complex DNA-based functional nanoscale structures. However, when DNA functional and responsive units that are based on non-canonical DNA interactions are employed it becomes quite challenging to predict, understand and control their thermodynamics. In response to this limitation, here we demonstrate the use of isothermal urea titration experiments to estimate the free energy involved in a set of DNA-based systems ranging from unimolecular DNA-based nanoswitches to more complex DNA folds (e...
June 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28600959/beyond-the-canonical-strategies-of-horizontal-gene-transfer-in-prokaryotes
#17
REVIEW
Cristina García-Aljaro, Elisenda Ballesté, Maite Muniesa
Efforts to identify and characterize strategies for horizontal gene transfer (HGT) in prokaryotes could have overlooked some mechanisms that do not entirely fit in with the canonical ones most often described (conjugation of plasmids, phage transduction and transformation). The difficulty in distinguishing the different HGT strategies could have contributed to underestimate their real extent. Here we review non classical HGT strategies: some that require mobile genetic elements (MGEs) and others independent of MGE...
June 7, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/28592536/evasion-of-the-sting-dna-sensing-pathway-by-the-vp11-12-of-herpes-simplex-virus-type-1
#18
Thibaut Deschamps, Maria Kalamvoki
The STimulator of INterferon Genes (STING) is a broad antimicrobial factor that restricts HSV by activating type I interferon and pro-inflammatory responses upon sensing of foreign DNA. UL46 is one of the most abundant tegument proteins of HSV-1 but a well-established function has yet to be found. We found that the HSV-1 UL46 protein interacts with and co-localizes with STING. A ΔUL46 virus displayed growth defects and activated innate immunity but both effects were alleviated in STING-knockdown cells. UL46 was also required for the inhibition of the 2' 3' -cGAMP-dependent immune responses during infection...
June 7, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28586299/inter-fork-strand-annealing-causes-genomic-deletions-during-the-termination-of-dna-replication
#19
Carl A Morrow, Michael O Nguyen, Andrew Fower, Io Nam Wong, Fekret Osman, Claire Bryer, Matthew C Whitby
Problems that arise during DNA replication can drive genomic alterations that are instrumental in the development of cancers and many human genetic disorders. Replication fork barriers are a commonly encountered problem, which can cause fork collapse and act as hotspots for replication termination. Collapsed forks can be rescued by homologous recombination, which restarts replication. However, replication restart is relatively slow and, therefore, replication termination may frequently occur by an active fork converging on a collapsed fork...
June 6, 2017: ELife
https://www.readbyqxmd.com/read/28584239/the-effect-of-the-neutral-cytidine-protonated-analogue-pseudoisocytidine-on-the-stability-of-i-motif-structures
#20
B Mir, X Solés, C González, N Escaja
Incorporation of pseudoisocytidine (psC), a neutral analogue of protonated cytidine, in i-motifs has been studied by spectroscopic methods. Our results show that neutral psC:C base pairs can stabilize i-motifs at neutral pH, but the stabilization only occurs when psC:C base pairs are located at the ends of intercalated C:C(+) stacks. When psC occupies central positions, the resulting i-motifs are only observed at low pH and psC:C(+) or psC:psC(+) hemiprotonated base pairs are formed instead of their neutral analogs...
June 5, 2017: Scientific Reports
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