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Nucleic Acids Research

Sumirtha Balaratnam, Nicole West, Soumitra Basu
The piwi interacting RNAs (piRNAs) are small non-coding RNAs that specifically bind to the PIWI proteins, a functional requirement. The piRNAs regulate germline development, transposons control, and gene expression. However, piRNA-mediated post-transcriptional gene regulation in human somatic cells is not well understood. We discovered a human piRNA (piR-FTH1) which has a complementary sequence in the ferritin heavy chain 1 (Fth1) mRNA. We demonstrated that expression of piR-FTH1 and Fth1 are inversely correlated in the tested tumor cell lines...
August 9, 2018: Nucleic Acids Research
Sneha Gopalan, Dana M Gibbon, Charles A S Banks, Ying Zhang, Laurence A Florens, Michael P Washburn, Preeti Dabas, Nimisha Sharma, Christopher W Seidel, Ronald C Conaway, Joan W Conaway
ELL family transcription factors activate the overall rate of RNA polymerase II (Pol II) transcription elongation by binding directly to Pol II and suppressing its tendency to pause. In metazoa, ELL regulates Pol II transcription elongation as part of a large multisubunit complex referred to as the Super Elongation Complex (SEC), which includes P-TEFb and EAF, AF9 or ENL, and an AFF family protein. Although orthologs of ELL and EAF have been identified in lower eukaryotes including Schizosaccharomyces pombe, it has been unclear whether SEC-like complexes function in lower eukaryotes...
August 9, 2018: Nucleic Acids Research
Maxim Tikhonov, Marina Utkina, Oksana Maksimenko, Pavel Georgiev
Alternative splicing (AS) is a regulatory mechanism of gene expression that greatly expands the coding capacities of genomes by allowing the generation of multiple mRNAs from a single gene. In Drosophila, the mod(mdg4) locus is an extreme example of AS that produces more than 30 different mRNAs via trans-splicing that joins together the common exons and the 3' variable exons generated from alternative promoters. To map the regions required for trans-splicing, we have developed an assay for measuring trans-splicing events and identified a 73-bp region in the last common intron that is critical for trans-splicing of three pre-mRNAs synthesized from different DNA strands...
August 9, 2018: Nucleic Acids Research
Lei Wang, Yosuke Taniguchi, Hidenori Okamura, Shigeki Sasaki
The antigene strategy based on site-specific recognition of duplex DNA by triplex DNA formation has been exploited in a wide range of biological activities. However, specific triplex formation is mostly restricted to homo-purine strands within the target duplex DNA, due to the destabilizing effect of CG and TA inversion sites where there is an absence of natural nucleotides that can recognize the CG and TA base pairs. Hence, the design of artificial nucleosides, which can selectively recognize these inversion sites with high affinity, should be of great significance...
August 8, 2018: Nucleic Acids Research
Ayyappasamy Sudalaiyadum Perumal, Rishi Kishore Vishwakarma, Yangbo Hu, Zakia Morichaud, Konstantin Brodolin
The transcriptional activator RbpA associates with Mycobacterium tuberculosis RNA polymerase (MtbRNAP) during transcription initiation, and stimulates formation of the MtbRNAP-promoter open complex (RPo). Here, we explored the influence of promoter motifs on RbpA-mediated activation of MtbRNAP containing the stress-response σB subunit. We show that both the 'extended -10' promoter motif (T-17G-16T-15G-14) and RbpA stabilized RPo and allowed promoter opening at suboptimal temperatures. Furthermore, in the presence of the T-17G-16T-15G-14 motif, RbpA was dispensable for RNA synthesis initiation, while exerting a stabilization effect on RPo...
August 8, 2018: Nucleic Acids Research
Matteo De March, Susana Barrera-Vilarmau, Emmanuele Crespan, Elisa Mentegari, Nekane Merino, Amaia Gonzalez-Magaña, Miguel Romano-Moreno, Giovanni Maga, Ramon Crehuet, Silvia Onesti, Francisco J Blanco, Alfredo De Biasio
p15PAF is an oncogenic intrinsically disordered protein that regulates DNA replication and lesion bypass by interacting with the human sliding clamp PCNA. In the absence of DNA, p15PAF traverses the PCNA ring via an extended PIP-box that contacts the sliding surface. Here, we probed the atomic-scale structure of p15PAF-PCNA-DNA ternary complexes. Crystallography and MD simulations show that, when p15PAF occupies two subunits of the PCNA homotrimer, DNA within the ring channel binds the unoccupied subunit. The structure of PCNA-bound p15PAF in the absence and presence of DNA is invariant, and solution NMR confirms that DNA does not displace p15PAF from the ring wall...
August 8, 2018: Nucleic Acids Research
Milena Jaskólska, Sandrine Stutzmann, Candice Stoudmann, Melanie Blokesch
During growth on chitinous surfaces in its natural aquatic environment Vibrio cholerae develops natural competence for transformation and kills neighboring non-immune bacteria using a type VI secretion system (T6SS). Activation of these two phenotypes requires the chitin-induced regulator TfoX, but also integrates signals from quorum sensing via the intermediate regulator QstR, which belongs to the LuxR-type family of regulators. Here, we define the QstR regulon using RNA sequencing. Moreover, by mapping QstR binding sites using chromatin immunoprecipitation coupled with deep sequencing we demonstrate that QstR is a transcription factor that binds upstream of the up- and down-regulated genes...
August 8, 2018: Nucleic Acids Research
David S Fischer, Fabian J Theis, Nir Yosef
Temporal changes to the concentration of molecular species such as mRNA, which take place in response to various environmental cues, can often be modeled as simple continuous functions such as a single pulse (impulse) model. The simplicity of such functional representations can provide an improved performance on fundamental tasks such as noise reduction, imputation and differential expression analysis. However, temporal gene expression profiles are often studied with models that treat time as a categorical variable, neglecting the dependence between time points...
August 8, 2018: Nucleic Acids Research
Ben Niu, Denise M Coslo, Alain R Bataille, Istvan Albert, B Franklin Pugh, Curtis J Omiecinski
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses...
August 8, 2018: Nucleic Acids Research
Jianping Lu, Juan Xu, Junyi Li, Tao Pan, Jing Bai, Liqiang Wang, Xiyun Jin, Xiaoyu Lin, Yunpeng Zhang, Yongsheng Li, Nidhi Sahni, Xia Li
Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs). However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers. Here, we performed genome-wide analyses and constructed molecular signatures and network profiles of functional CRs in over 10 000 tumors across 33 cancer types. By integration of DNA mutation, genome-wide methylation, transcriptional/post-transcriptional regulation, and protein interaction networks with clinical outcomes, we identified CRs associated with cancer subtypes and clinical prognosis as potential oncogenic drivers...
August 8, 2018: Nucleic Acids Research
Lei Feng, Chen-Chen Chang, Dong Song, Chuang Jiang, Yang Song, Chao-Fan Wang, Wei Deng, Ya-Juan Zou, Hai-Feng Chen, Xiang Xiao, Feng-Ping Wang, Xi-Peng Liu
Nucleases play important roles in nucleic acid metabolism. Some archaea encode a conserved protein known as Hef-associated nuclease (HAN). In addition to its C-terminal DHH nuclease domain, HAN also has three N-terminal domains, including a DnaJ-Zinc-finger, ribosomal protein S1-like, and oligonucleotide/oligosaccharide-binding fold. To further understand HAN's function, we biochemically characterized the enzymatic properties of HAN from Pyrococcus furiosus (PfuHAN), solved the crystal structure of its DHH nuclease domain, and examined its role in DNA repair...
August 8, 2018: Nucleic Acids Research
Brittany S Morgan, Jordan E Forte, Amanda E Hargrove
Over the past decade, the RNA revolution has revealed thousands of non-coding RNAs that are essential for cellular regulation and are misregulated in disease. While the development of methods and tools to study these RNAs has been challenging, the power and promise of small molecule chemical probes is increasingly recognized. To harness existing knowledge, we compiled a list of 116 ligands with reported activity against RNA targets in biological systems (R-BIND). In this survey, we examine the RNA targets, design and discovery strategies, and chemical probe characterization techniques of these ligands...
August 8, 2018: Nucleic Acids Research
Patrick Keller, Isabel Freund, Virginie Marchand, Guillaume Bec, Raven Huang, Yuri Motorin, Tatjana Eigenbrod, Alexander Dalpke, Mark Helm
Sensing of nucleic acids for molecular discrimination between self and non-self is a challenging task for the innate immune system. RNA acts as a potent stimulus for pattern recognition receptors including in particular human Toll-like receptor 7 (TLR7). Certain RNA modifications limit potentially harmful self-recognition of endogenous RNA. Previous studies had identified the 2'-O-methylation of guanosine 18 (Gm18) within tRNAs as an antagonist of TLR7 leading to an impaired immune response. However, human tRNALys3 was non-stimulatory despite lacking Gm18...
August 8, 2018: Nucleic Acids Research
Donghyun Ka, Dong Man Jang, Byung Woo Han, Euiyoung Bae
Clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins provide microbial adaptive immunity against invading foreign nucleic acids. In type II-A CRISPR-Cas systems, the Cas1-Cas2 integrase complex and the subtype-specific Csn2 comprise the CRISPR adaptation module, which cooperates with the Cas9 nuclease effector for spacer selection. Here, we report the molecular organization of the Streptococcus pyogenes type II-A CRISPR adaptation module and its interaction with Cas9 via Csn2...
August 8, 2018: Nucleic Acids Research
Krister J Barkovich, Megan K Moore, Qi Hu, Kevan M Shokat
DEAD-box proteins are an essential class of enzymes involved in all stages of RNA metabolism. The study of DEAD-box proteins is challenging in a native setting since they are structurally similar, often essential and display dosage sensitivity. Pharmacological inhibition would be an ideal tool to probe the function of these enzymes. In this work, we describe a chemical genetic strategy for the specific inactivation of individual DEAD-box proteins with small molecule inhibitors using covalent complementarity...
August 8, 2018: Nucleic Acids Research
Chringma Sherpa, Jason W Rausch, Stuart F J Le Grice
Long non-coding RNAs (lncRNAs) have emerged as key players in gene regulation. However, our incomplete understanding of the structure of lncRNAs has hindered molecular characterization of their function. Maternally expressed gene 3 (Meg3) lncRNA is a tumor suppressor that is downregulated in various types of cancer. Mechanistic studies have reported a role for Meg3 in epigenetic regulation by interacting with chromatin-modifying complexes such as the polycomb repressive complex 2 (PRC2), guiding them to genomic sites via DNA-RNA triplex formation...
August 8, 2018: Nucleic Acids Research
Arumugam Rajavelu, Cristiana Lungu, Max Emperle, Michael Dukatz, Alexander Bröhm, Julian Broche, Ines Hanelt, Edris Parsa, Sarah Schiffers, Rahul Karnik, Alexander Meissner, Thomas Carell, Philipp Rathert, Renata Z Jurkowska, Albert Jeltsch
Despite their central importance in mammalian development, the mechanisms that regulate the DNA methylation machinery and thereby the generation of genomic methylation patterns are still poorly understood. Here, we identify the 5mC-binding protein MeCP2 as a direct and strong interactor of DNA methyltransferase 3 (DNMT3) proteins. We mapped the interaction interface to the transcriptional repression domain of MeCP2 and the ADD domain of DNMT3A and find that binding of MeCP2 strongly inhibits the activity of DNMT3A in vitro...
August 8, 2018: Nucleic Acids Research
Qinyu Sun, Vidisha Tripathi, Je-Hyun Yoon, Deepak K Singh, Qinyu Hao, Kyung-Won Min, Sylvia Davila, Richard W Zealy, Xiao Ling Li, Maria Polycarpou-Schwarz, Elin Lehrmann, Yongqing Zhang, Kevin G Becker, Susan M Freier, Yuelin Zhu, Sven Diederichs, Supriya G Prasanth, Ashish Lal, Myriam Gorospe, Kannanganattu V Prasanth
Long non-coding RNAs (lncRNAs) regulate vital biological processes, including cell proliferation, differentiation and development. A subclass of lncRNAs is synthesized from microRNA (miRNA) host genes (MIRHGs) due to pre-miRNA processing, and are categorized as miRNA-host gene lncRNAs (lnc-miRHGs). Presently, the cellular function of most lnc-miRHGs is not well understood. We demonstrate a miRNA-independent role for a nuclear-enriched lnc-miRHG in cell cycle progression. MIR100HG produces spliced and stable lncRNAs that display elevated levels during the G1 phase of the cell cycle...
August 8, 2018: Nucleic Acids Research
Roberto Paredes, Marion Schneider, Adam Stevens, Daniel J White, Andrew J K Williamson, Joanne Muter, Stella Pearson, James R Kelly, Kathleen Connors, Daniel H Wiseman, John A Chadwick, Harald Löffler, Hsiang Ying Teng, Simon Lovell, Richard Unwin, Henri J van de Vrugt, Helen Smith, Olga Kustikova, Axel Schambach, Tim C P Somervaille, Andrew Pierce, Anthony D Whetton, Stefan Meyer
No abstract text is available yet for this article.
August 8, 2018: Nucleic Acids Research
Stefan Dexl, Robert Reichelt, Katharina Kraatz, Sarah Schulz, Dina Grohmann, Michael Bartlett, Michael Thomm
Transcription initiation by archaeal RNA polymerase (RNAP) and eukaryotic RNAP II requires the general transcription factor (TF) B/ IIB. Structural analyses of eukaryotic transcription initiation complexes locate the B-reader domain of TFIIB in close proximity to the active site of RNAP II. Here, we present the first crosslinking mapping data that describe the dynamic transitions of an archaeal TFB to provide evidence for structural rearrangements within the transcription complex during transition from initiation to early elongation phase of transcription...
August 8, 2018: Nucleic Acids Research
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