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Featured Articles - July 2013

Featured Articles highlight the best papers published in NAR. These articles are chosen by the Executive Editors on the recommendation of Editorial Board Members and Referees. They represent the top 5% of papers in terms of originality, significance and scientific excellence. The articles are accompanied by a brief synopsis explaining the findings of the paper and where they fit in the broader context of nucleic acids research.

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Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation
Sun C, Querol-Audí J, Mortimer SA, Arias-Palomo E, Doudna JA, Nogales E, Cate JH.

Functionally reconstituted eIF3 in E. coli and electron microscopy were used to identify two previously unknown but critical RNA binding motifs in eIF3 that control start codon selection and downstream steps of translation initiation. Mutations in these motifs disrupt initiation on the hepatitis C virus Internal Ribosome Entry Site (HCV IRES). Based on their conservation and the common requirements for cellular and HCV IRES-mediate translation, these RNA binding motifs are likely to be important for the translation of the human transcriptome. Read on

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Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells
Holwerda SJ, van de Werken HJ, Ribeiro de Almeida C, Bergen IM, de Bruijn MJ, Verstegen MJ, Simonis M, Splinter E, Wijchers PJ, Hendriks RW, de Laat W.

The IgH locus encodes for part of the antibody exposed by B cells and is important for the immune system. In B cells, one allele produces protein, the other must remain silenced. It was proposed that both alleles reside in different nuclear compartments and that this is important to maintain mono-allelic productivity. Here the authors have challenged this concept. They produced detailed genome-wide contact maps, which show that IgH adopts different nuclear locations in immune versus other cells, but also demonstrate that in B cells both alleles reside in the same environment. Nuclear positioning is therefore not important to maintain allelic exclusion. Read on

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Investigation of DNA sequence recognition by a streptomycete MarR family transcriptional regulator through surface plasmon resonance and X-ray crystallography
Stevenson CE, Assaad A, Chandra G, Le TB, Greive SJ, Bibb MJ, Lawson DM.

The authors describe novel generic Surface Plasmon Resonance protocols to identify and footprint protein-DNA interactions in a semi-automated and cost-effective manner. Specifically, they locate binding sites for a bacterial transcription factor and delineate the extent of the protein footprint on the DNA. They subsequently verify these observations through X-ray crystallography. This work will appeal to those with interests in transcriptional regulation and, more generally, those investigating protein-nucleic acid interactions. These simple methods will attract much interest from this community as they offer viable, label-free alternatives to more traditional methods, such as electrophoretic mobility shift assays and DNase I footprinting. Read on

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Hepatitis C virus 3’UTR regulates viral translation through direct interactions with the host translation machinery
Bai Y, Zhou K, Doudna JA.

This study addresses the fundamental question of how viral RNA structures recruit and regulate the cellular translation machinery to enable efficient protein synthesis. The molecular insights into function of the 3’UTR of the hepatitis C virus (HCV) provided by this work offer both a breakthrough in fundamental understanding and the potential for new anti-HCV therapeutic strategies. Read on

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Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes
Pedersen BS, De S.

Loss of heterozygosity (LOH) is a type of genetic abnormality frequently found in cancer genomes, by which genetic differences between paternal and maternal copies of a genomic locus are removed. Analyzing data for a large number of cancer genomes, the authors propose that during early replication, rescue of replication using homologous chromosomes as template leads to LOH. In early replicating regions, LOH mediated gene conversion can potentially replace wild-type alleles with recessive deleterious alleles, leading to increased risk of recessive deleterious traits. Furthermore, the difference in replication timing preference between different classes of genomic alterations also provokes a testable hypothesis that replicating cells show changing preference between various DNA repair pathways as the replication progresses. Read on

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Structural insight into negative DNA supercoiling by DNA gyrase, a bacterial type 2A DNA topoisomerase
Papillon J, Ménétret JF, Batisse C, Hélye R, Schultz P, Potier N, Lamour V.

DNA topoisomerases are essential cellular enzymes that regulate the topology of DNA. The bacterial DNA gyrase has the unique property to introduce negative supercoils in DNA molecules by the reversible cleavage of duplex DNA allowing the transport of another DNA through this transient break upon ATP hydrolysis. This cryo-electron microscopy study reveals the full architecture of this modular enzyme wrapping a long stretch of 149 bp duplex DNA and blocked by the fluoroquinolone antibiotic ciprofloxacin. These data suggest that the enzyme ATP binding and C-terminal domains cooperate to trap DNA crossovers and that ciprofloxacin targets a DNA pre-transport conformation. Read on

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BeEP Server: using evolutionary information for quality assessment of protein structure models
Palopoli N, Lanzarotti E, Parisi G.

The BeEP Server applies evolutionary information to the prediction of three-dimensional models of protein structure. The BeEP method estimates how constraints imposed by structure can influence the evolution of a protein, and given different models of the same protein, it ranks them on the basis of how well they represent the evolutionary pattern observed in nature. Best models can thus be identified for further exploration. BeEP is available at http://www.embnet.qb.fcen.uba.ar/embnet/beep.php. Read on

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PELE Web Server: atomistic study of biomolecular systems at your fingertips
Madadkar-Sobhani A, Guallar V.

PELE - Protein Energy Landscape Exploration, which is based on protein structure prediction algorithms and a Monte Carlo sampling, is capable of quickly and efficiently modeling all-atom protein-ligand dynamic interactions. It provides two orders of magnitude reduced computational cost when compared to traditional molecular dynamics techniques. PELE is available at http://pele.bsc.es. Read on

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Computational identification of novel biochemical systems involved in oxidation, glycosylation and other complex modifications of bases in DNA
Iyer LM, Zhang D, Maxwell Burroughs A, Aravind L.

Using sensitive computational methods the authors characterize several novel biochemical systems for DNA modifications, such as the J-base generating glycosyltransferase of kinetoplastids. They also predict the enzymes involved in synthesis of hypermodified bases such as alpha-glutamylthymine and alpha-putrescinylthymine that have remained enigmatic for several decades. This article presents evidence that some of these modification systems are also widely dispersed across prokaryotes and certain eukaryotes such as mushroom and alga. This study extends the role of the PUA-like fold domains in recognition of modified nucleic acids. These results open opportunities for investigation of the biology of these systems and their use in biotechnology. Read on