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https://www.readbyqxmd.com/read/28781234/structural-basis-for-the-canonical-and-non-canonical-pam-recognition-by-crispr-cpf1
#1
Takashi Yamano, Bernd Zetsche, Ryuichiro Ishitani, Feng Zhang, Hiroshi Nishimasu, Osamu Nureki
The RNA-guided Cpf1 (also known as Cas12a) nuclease associates with a CRISPR RNA (crRNA) and cleaves the double-stranded DNA target complementary to the crRNA guide. The two Cpf1 orthologs from Acidaminococcus sp. (AsCpf1) and Lachnospiraceae bacterium (LbCpf1) have been harnessed for eukaryotic genome editing. Cpf1 requires a specific nucleotide sequence, called a protospacer adjacent motif (PAM), for target recognition. Besides the canonical TTTV PAM, Cpf1 recognizes suboptimal C-containing PAMs. Here, we report four crystal structures of LbCpf1 in complex with the crRNA and its target DNA containing either TTTA, TCTA, TCCA, or CCCA as the PAM...
August 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28765009/involvement-of-trnas-in-replication-of-human-mitochondrial-dna-and-modifying-effects-of-telomerase
#2
Meenakshisundaram Balasubramaniam, Robert J Shmookler Reis, D Phil, Srinivas Ayyadevara, Xianwei Wang, Akshatha Ganne, Magomed Khaidakov
Overexpression of telomerase has been shown to significantly increase the lifespan of mice. When mechanistically attributed to repair of critically short telomeres, the lifespan extending action of telomerase cannot be reconciled with the observation that telomerase-null mice do not exhibit shortening of lifespan for at least two generations. We hypothesized that telomerase may interfere with replication of mitochondrial DNA (mtDNA) in a way that reduces formation of deletions - the primary cause of age-dependent cell attrition in non-renewable cells such as myocytes and neurons...
July 29, 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28763217/characterization-of-g4-g4-crosstalk-in-c-kit-promoter-region
#3
Riccardo Rigo, Claudia Sissi
The proximal promoter of c-KIT contains a peculiar domain that comprise three closely located short G-rich sequences able to fold into non-canonical DNA secondary structures called G-quadruplexes (G4). Here, we focused on a sequence corresponding to two consecutive G4 forming (kit2 and kit*) and, by electrophoretic, SPR and spectroscopic techniques, we demon-strated that they retain the ability to fold into G4 when inserted in the extended sequence. Noteworthy, we highlighted the occurrence of a crosstalk between the two forming units...
August 1, 2017: Biochemistry
https://www.readbyqxmd.com/read/28758290/crystal-structure-of-master-biofilm-regulator-csgd-regulatory-domain-reveals-an-atypical-receiver-domain
#4
Yurong Wen, Zhenlin Ouyang, Bart Devreese, Wangxiao He, Yongping Shao, Wuyuan Lu, Fang Zheng
The master regulator CsgD switches planktonic growth to biofilm formation by activating synthesis of curli fimbriae and cellulose in Enterobacteriaceae. CsgD was classified to be the LuxR response regulatory family, while its cognate sensor histidine kinase has not been identified yet. CsgD consists of a C-terminal DNA binding domain and an N-terminal regulatory domain that provokes the upstream signal transduction to further modulate its function. We provide the crystal structure of Salmonella Typhimurium CsgD regulatory domain, which reveals an atypical β5α5 response regulatory receiver domain folding with the α2 helix representing as a disorder loop compared to the LuxR/FixJ canonical response regulator, and the structure indicated a noteworthy α5 helix similar to the non-canonical master regulator VpsT receiver domain α6...
July 30, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28754468/microhomology-mediated-end-joining-good-bad-and-ugly
#5
REVIEW
Ja-Hwan Seol, Eun Yong Shim, Sang Eun Lee
DNA double-strand breaks (DSBs) are induced by a variety of genotoxic agents, including ionizing radiation and chemotherapy drugs for treating cancers. The elimination of DSBs proceeds via distinctive error-free and error-prone pathways. Repair by homologous recombination (HR) is largely error-free and mediated by RAD51/BRCA2 gene products. Classical non-homologous end joining (C-NHEJ) requires the Ku heterodimer and can efficiently rejoin breaks, with occasional loss or gain of DNA information. Recently, evidence has unveiled another DNA end-joining mechanism that is independent of recombination factors and Ku proteins, termed alternative non-homologous end joining (A-NHEJ)...
July 16, 2017: Mutation Research
https://www.readbyqxmd.com/read/28740723/at-the-interface-of-three-nucleic-acids-the-role-of-rna-binding-proteins-and-poly-adp-ribose-in-dna-repair
#6
E E Alemasova, O I Lavrik
RNA-binding proteins (RBPs) regulate RNA metabolism, from synthesis to decay. When bound to RNA, RBPs act as guardians of the genome integrity at different levels, from DNA damage prevention to the post-transcriptional regulation of gene expression. Recently, RBPs have been shown to participate in DNA repair. This fact is of special interest as DNA repair pathways do not generally involve RNA. DNA damage in higher organisms triggers the formation of the RNA-like polymer - poly(ADP-ribose) (PAR). Nucleic acid-like properties allow PAR to recruit DNA- and RNA-binding proteins to the site of DNA damage...
April 2017: Acta Naturae
https://www.readbyqxmd.com/read/28729824/mouse-models-of-c9orf72-hexanucleotide-repeat-expansion-in-amyotrophic-lateral-sclerosis-frontotemporal-dementia
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
Marek Havrila, Petr Stadlbauer, Barira Islam, Michal Otyepka, Jiří Šponer
G-quadruplexes (GQs) are key noncanonical 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 11 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...
July 17, 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
#15
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
#16
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...
August 4, 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
#17
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
#18
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
#19
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
#20
Kensuke Tateishi, Fumi Higuchi, Julie J Miller, Mara V A Koerner, Nina Lelic, Ganesh M Shankar, Shota Tanaka, David E Fisher, Tracy T Batchelor, A John Iafrate, Hiroaki Wakimoto, Andrew S Chi, Daniel P Cahill
IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD(+) for survival. It is known that 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 could potentiate NAD(+) depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of temozolomide on NAD(+) metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD(+) biosynthesis...
August 1, 2017: Cancer Research
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