Journal Articles
FANCD2 and REV1 cooperate in the protection of nascent DNA strands in response to replication stress
REV1 is a eukaryotic member of the Y-family of DNA polymerases involved in translesion DNA synthesis and genome mutagenesis. Recently, REV1 is also found to function in homologous recombination. However, it remains unclear how REV1 is recruited to the sites where homologous recombination is processed. Here, we report that loss of mammalian REV1 results in a specific defect in replication-associated gene conversion. We found that REV1 is targeted to laser-induced DNA damage stripes in a manner dependent on its ubiquitin-binding motifs, on RAD18, and on monoubiquitinated FANCD2 (FANCD2-mUb) that associates with REV1. Expression of a FANCD2-Ub chimeric protein in RAD18-depleted cells enhances REV1 assembly at laser-damaged sites, suggesting that FANCD2-mUb functions downstream of RAD18 to recruit REV1 to DNA breaks. Consistent with this suggestion we found that REV1 and FANCD2 are epistatic with respect to sensitivity to the double-strand break-inducer camptothecin. REV1 enrichment at DNA damage stripes also partially depends on BRCA1 and BRCA2, components of the FANCD2/BRCA supercomplex. Intriguingly, analogous to FANCD2-mUb and BRCA1/BRCA2, REV1 plays an unexpected role in protecting nascent replication tracts from degradation by stabilizing RAD51 filaments. Collectively these data suggest that REV1 plays multiple roles at stalled replication forks in response to replication stress.
DNA polymerases {kappa} and {zeta} cooperatively perform mutagenic translesion synthesis of the C8-2'-deoxyguanosine adduct of the dietary mutagen IQ in human cells
The roles of translesion synthesis (TLS) DNA polymerases in bypassing the C8–2'-deoxyguanosine adduct (dG-C8-IQ) formed by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a highly mutagenic and carcinogenic heterocyclic amine found in cooked meats, were investigated. Three plasmid vectors containing the dG-C8-IQ adduct at the G1-, G2- or G3-positions of the NarI site (5'-G1G2CG3CC-3') were replicated in HEK293T cells. Fifty percent of the progeny from the G3 construct were mutants, largely G->T, compared to 18% and 24% from the G1 and G2 constructs, respectively. Mutation frequency (MF) of dG-C8-IQ was reduced by 38–67% upon siRNA knockdown of pol , whereas it was increased by 10–24% in pol knockdown cells. When pol and pol were simultaneously knocked down, MF of the G1 and G3 constructs was reduced from 18% and 50%, respectively, to <3%, whereas it was reduced from 24% to <1% in the G2 construct. In vitro TLS using yeast pol showed that it can extend G3*:A pair more efficiently than G3*:C pair, but it is inefficient at nucleotide incorporation opposite dG-C8-IQ. We conclude that pol and pol cooperatively carry out the majority of the error-prone TLS of dG-C8-IQ, whereas pol is involved primarily in its error-free bypass.
VEGAWES: variational segmentation on whole exome sequencing for copy number detection
Label noise in subtype discrimination of class C G protein-coupled receptors: A systematic approach to the analysis of classification errors
methylPipe and compEpiTools: a suite of R packages for the integrative analysis of epigenomics data
NetBenchmark: a bioconductor package for reproducible benchmarks of gene regulatory network inference
PROKARYO: an illustrative and interactive computational model of the lactose operon in the bacterium <it>Escherichia coli</it>
Methods of model accuracy estimation can help selecting the best models from decoy sets: Assessment of model accuracy estimations in CASP11
The article presents assessment of the model accuracy estimation methods participating in CASP11. The results of the assessment are expected to be useful to both—developers of the methods and users who way too often are presented with structural models without annotations of accuracy. The main emphasis is placed on the ability of techniques to identify the best models from among several available. Bivariate descriptive statistics and ROC analysis are used to additionally assess the overall correctness of the predicted model accuracy scores, the correlation between the predicted and observed accuracy of models, the effectiveness in distinguishing between good and bad models, the ability to discriminate between reliable and unreliable regions in models, and the accuracy of the coordinate error self-estimates. A rigid-body measure (GDT_TS) and three local-structure-based scores (LDDT, CADaa, and SphereGrinder) are used as reference measures for evaluating methods' performance. Consensus methods, taking advantage of the availability of several models for the same target protein, perform well on the majority of tasks. Methods that predict accuracy on the basis of a single model perform comparably to consensus methods in picking the best models and in the estimation of how accurate is the local structure. More groups than in previous experiments submitted reasonable error estimates of their own models, most likely in response to a recommendation from CASP and the increasing demand from users. Proteins 2015. © 2015 Wiley Periodicals, Inc.
In silico mutational studies of Hsp70 disclose sites with distinct functional attributes
The Mutation-Minimization Method (MuMi) to study the local response of proteins to point mutations has been introduced here. The heat shock protein Hsp70 as the test system since it displays features that have been studied in great detail has been used here. It has many conserved residues, serves several different functions on each of its domains, and displays interdomain allostery. For the analysis of spatial arrangement of residues within the protein, the network properties of the wild type (WT) protein as well as its all single alanine residue mutants using MuMi has been investigated. The measures to express the amount of change from the WT structure upon mutation and compare these deviations to find potential critical sites have been proposed. The functional significance of the potential sites to the parameter that uncovers them has been mapped. It was found that sites directly involved in binding were sensitive to mutations and were characterized by large displacements. On the other hand, sites that steer large conformational changes typically had increased reachability upon alanine mutations occurring elsewhere in the protein. Finally, residues that control communication within and between domains reside on the largest number of paths connecting pairs of residues in the protein. Proteins 2015; 83:2077–2090. © 2015 Wiley Periodicals, Inc.
Correction to “Copper(I)-Catalyzed Borylative exo-Cyclization of Alkenyl Halides Containing Unactivated Double Bond”
Nanostructure of Materials Determined by Relayed Paramagnetic Relaxation Enhancement
Crystal Facets Make a Profound Difference in Polyoxometalate-Containing Metal–Organic Frameworks as Catalysts for Biodiesel Production
Synthesis and Characterization of Poly(glyceric Acid Carbonate): A Degradable Analogue of Poly(acrylic Acid)
Electron Hopping through Double-Exchange Coupling in a Mixed-Valence Diiminobenzoquinone-Bridged Fe2 Complex
CATCHing putative causative variants in consanguineous families
General Method for the Synthesis of Ultrastable Core/Shell Quantum Dots by Aluminum Doping
BCL::MP-fold: Membrane protein structure prediction guided by EPR restraints
For many membrane proteins, the determination of their topology remains a challenge for methods like X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. Electron paramagnetic resonance (EPR) spectroscopy has evolved as an alternative technique to study structure and dynamics of membrane proteins. The present study demonstrates the feasibility of membrane protein topology determination using limited EPR distance and accessibility measurements. The BCL::MP-Fold (BioChemical Library membrane protein fold) algorithm assembles secondary structure elements (SSEs) in the membrane using a Monte Carlo Metropolis (MCM) approach. Sampled models are evaluated using knowledge-based potential functions and agreement with the EPR data and a knowledge-based energy function. Twenty-nine membrane proteins of up to 696 residues are used to test the algorithm. The RMSD100 value of the most accurate model is better than 8 Å for 27, better than 6 Å for 22, and better than 4 Å for 15 of the 29 proteins, demonstrating the algorithms' ability to sample the native topology. The average enrichment could be improved from 1.3 to 2.5, showing the improved discrimination power by using EPR data. Proteins 2015; 83:1947–1962. © 2015 Wiley Periodicals, Inc
Prediction of the substrate for nonribosomal peptide synthetase (NRPS) adenylation domains by virtual screening
Nonribosomal peptide synthetases (NRPSs) synthesize a diverse array of bioactive small peptides, many of which are used in medicine. There is considerable interest in predicting NRPS substrate specificity in order to facilitate investigation of the many “cryptic” NRPS genes that have not been linked to any known product. However, the current sequence similarity-based methods are unable to produce reliable predictions when there is a lack of prior specificity data, which is a particular problem for fungal NRPSs. We conducted virtual screening on the specificity-determining domain of NRPSs, the adenylation domain, and found that virtual screening using experimentally determined structures results in good enrichment of the cognate substrate. Our results indicate that the conformation of the adenylation domain and in particular the conformation of a key conserved aromatic residue is important in determining the success of the virtual screening. When homology models of NRPS adenylation domains of known specificity, rather than experimentally determined structures, were built and used for virtual screening, good enrichment of the cognate substrate was also achieved in many cases. However, the accuracy of the models was key to the reliability of the predictions and there was a large variation in the results when different models of the same domain were used. This virtual screening approach is promising and is able to produce enrichment of the cognate substrates in many cases, but improvements in building and assessing homology models are required before the approach can be reliably applied to these models. Proteins 2015; 83:2052–2066. © 2015 Wiley Periodicals, Inc.
Structural basis for gene regulation by a B12-dependent photoreceptor
Structural basis for gene regulation by a B12-dependent photoreceptor
Nature 526, 7574 (2015). doi:10.1038/nature14950
Authors: Marco Jost, Jésus Fernández-Zapata, María Carmen Polanco, Juan Manuel Ortiz-Guerrero, Percival Yang-Ting Chen, Gyunghoon Kang, S. Padmanabhan, Montserrat Elías-Arnanz & Catherine L. Drennan
Photoreceptor proteins enable organisms to sense and respond to light. The newly discovered CarH-type photoreceptors use a vitamin B12 derivative, adenosylcobalamin, as the light-sensing chromophore to mediate light-dependent gene regulation. Here we present crystal structures of Thermus thermophilus CarH in all three
50 & 100 Years Ago
50 & 100 Years Ago
Nature 525, 7570 (2015). doi:10.1038/525463a
50 Years AgoA Biological Retrospect. By Sir Peter Medawar — The title of my presidential address, as you will have discerned, is “A Biological Retrospect”, and on the whole it has not been well received. 'Why a biological retrospect?', I have been