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Measurement of acetylation turnover at distinct lysines in human histones identifies long-lived acetylation sites
Dynamic changes in histone acetylation are associated with regulation of gene expression. Zheng and colleagues develop a metabolic labelling technique that facilitates the measurement of acetylation turnover rates, and identify a group of sites whose acetylation is remarkably stable.
- Yupeng Zheng
- , Paul M. Thomas
- & Neil L. Kelleher
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DNA unmethylome profiling by covalent capture of CpG sites
Chemical modifications of CpG dinucleotides form part of the epigenetic code and various methods for the detection of modified CpG sites exist. Here Kriukiene and colleagues report a complementary method that allows the profiling of unmodified CpG sites within the genome, which they call the 'unmethylome'.
- Edita Kriukienė
- , Viviane Labrie
- & Saulius Klimašauskas
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The p53–PUMA axis suppresses iPSC generation
Inhibition of the p53–p21 axis increases reprogramming efficiency of somatic cells into induced pluripotent stem cells (iPSCs). Here the authors show that depletion of the pro-apoptotic factor PUMA, acting downstream of p53, increases reprogramming efficiency, providing new insights into the roles of p53 in reprogramming.
- Yanxin Li
- , Haizhong Feng
- & Tao Cheng
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| Open AccessMeta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2
Cancer-associated mutations in isocitrate dehydrogenase are proposed to impair TET2-dependent DNA demethylation. By comparing the methylomes of IDH-mutant cancers, the authors identify the transcription factor EBF1 as a partner of TET2, suggesting a possible means for targeting TET2 to specific DNA sequences.
- Paul Guilhamon
- , Malihe Eskandarpour
- & Stephan Beck
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Disparity between microRNA levels and promoter strength is associated with initiation rate and Pol II pausing
MicroRNAs are known to be transcribed by RNA polymerase II. The authors show that microRNA promoters driven by TATA-box or NF-κB have increased rates of transcription re-initiation, which leads to local crowding of RNA polymerase II and lower efficiency of microRNA synthesis.
- Nadav Marbach-Bar
- , Amitai Ben-Noon
- & Rivka Dikstein
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| Open AccessConformational landscapes of DNA polymerase I and mutator derivatives establish fidelity checkpoints for nucleotide insertion
The fidelity of DNA polymerases depends on conformational changes that promote the rejection of incorrect nucleotides. Here, by using an intramolecular single-molecule FRET assay, the authors establish and characterize the partially closed conformation as a crucial fidelity checkpoint.
- Johannes Hohlbein
- , Louise Aigrain
- & Achillefs N. Kapanidis
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| Open AccessR-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli
DNA double-strand breaks commonly occur in all replicating cells. Wimberly and colleagues show that in non-replicating cells, aborted transcription/translation forms RNA/DNA hybrid R-loops that prime origin-independent replication, leading to DNA breakage, point mutations and chromosomal rearrangements.
- Hallie Wimberly
- , Chandan Shee
- & P. J. Hastings
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| Open AccessThe thermodynamic patterns of eukaryotic genes suggest a mechanism for intron–exon recognition
The thermodynamics of unwinding polynucleotide duplexes can be determined from energy changes for DNA and mRNA interactions. Here the authors show that the ratio between mRNA/DNA and DNA/DNA duplex stability upstream of the 3′- spice sites is a characteristic that can contribute to intron–exon recognition.
- Marina N. Nedelcheva-Veleva
- , Mihail Sarov
- & Stoyno S. Stoynov
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A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing
Cdt1 is part of a protein complex that regulates the initiation of DNA replication. Here Coulombe et al. identify a PEST-like regulatory domain in the N terminus of Cdt1 that prevents premature initiation of DNA synthesis during the cell cycle.
- Philippe Coulombe
- , Damien Grégoire
- & Marcel Méchali
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DNA repair choice defines a common pathway for recruitment of chromatin regulators
Chromatin regulators facilitate repair of DNA double-strand breaks in chromosomal DNA. The authors show that the recruitment of such chromatin regulators to DNA lesions is controlled by the choice of DNA repair pathway.
- Gwendolyn Bennett
- , Manolis Papamichos-Chronakis
- & Craig L. Peterson
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Regulation of the DNA damage response on male meiotic sex chromosomes
The XY body is a structure required for silencing of sex chromosomes, which is enriched in DNA damage response proteins during meiosis in male germ cells. Here, the authors identify differences between the regulation of the DNA damage response at the XY body and in somatic cells.
- Lin-Yu Lu
- , Yi Xiong
- & Xiaochun Yu
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Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules
Myotonic dystrophy type 1 (DM1) is caused by defects in the alternative splicing of pre-mRNA. Childs-Disney and colleagues report two small molecules that either induce or reverse DM1-associated splicing defects by modulating the binding of pre-mRNA to muscleblind-like 1 protein.
- Jessica L. Childs-Disney
- , Ewa Stepniak-Konieczna
- & Matthew D. Disney
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| Open AccessFork sensing and strand switching control antagonistic activities of RecQ helicases
RecQ helicases are enzymes that play a central role in maintaining genome stability in the DNA repair cascade. Klaue et al. show that RecQ2 and RecQ3 from Arabidopsis thalianaprocess DNA by, respectively, unwinding and rewinding forked DNA substrates, using a frequent strand switching mechanism.
- Daniel Klaue
- , Daniela Kobbe
- & Ralf Seidel
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| Open AccessDynamics and stoichiometry of a regulated enhancer-binding protein in live Escherichia coli cells
Cellular adaptive responses require temporal and spatial control of key regulatory protein complexes. Mehta et al. describe the dynamic interaction of a transcriptional activator mediating membrane stress response in E. coliwith its negative regulator, the cell membrane and the transcription machinery.
- Parul Mehta
- , Goran Jovanovic
- & Martin Buck
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Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis
Changes in DNA methylation during mammalian spermatogenesis are poorly understood. The authors show that the content of 5-hydroxymethylcytosine, a stable intermediate of DNA demethylation, changes dynamically during mouse spermatogenesis and is associated with functional genomic regions and transcription.
- Haiyun Gan
- , Lu Wen
- & Fuchou Tang
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Deregulation of translation due to post-transcriptional modification of rRNA explains why erm genes are inducible
Erm methyltransferases confer antimicrobial drug resistance and their expression is induced by macrolides. Gupta et al.show that Erm-catalysed modification of rRNA affects synthesis of some proteins and reduces cell fitness, explaining why expression of Erm is deleterious in the absence of antibiotics.
- Pulkit Gupta
- , Shanmugapriya Sothiselvam
- & Alexander S. Mankin
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| Open AccessHaemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow-dependent expression of miR-21
microRNAs rapidly regulate gene expression and are implicated in cardiogenesis and angiogenesis. Banjo and colleagues show that the microRNA mir-21 is activated by the physical forces generated by blood flow, and that this regulates the development of heart valves in zebrafish.
- Toshihiro Banjo
- , Janin Grajcarek
- & Toshihiko Ogura
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Sam68 modulates the promoter specificity of NF-κB and mediates expression of CD25 in activated T cells
The NF-κB complex is a core regulator of inflammatory gene expression and activates transcription of many different target genes. Fu et al. show that NF-κB promoter specificity can be tuned by Sam68, which is required for targeting NF-κB to the CD25 promoter during T cell activation.
- Kai Fu
- , Xin Sun
- & Fengyi Wan
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| Open AccessAurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis
Geminin blocks the inappropriate assembly of pre-replication complexes on DNA, and this activity is inhibited in G1 by its proteasomal degradation. Tsunematsu et al.demonstrate that geminin is stabilized during mitosis due to its phosphorylation by the mitotic kinase Aurora-A.
- Takaaki Tsunematsu
- , Yoshihiro Takihara
- & Yasusei Kudo
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MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1
Lung cancers have a high potential to become metastatic, which is a major cause of treatment failure. Here, the authors identify a microRNA that is upregulated in non-small-cell lung cancer and is associated with Hippo pathway modulation metastasis and poor clinical outcome.
- Ching-Wen Lin
- , Yih-Leong Chang
- & Pan-Chyr Yang
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| Open AccessDirect imaging of single UvrD helicase dynamics on long single-stranded DNA
Tracking single molecules on long stretches of single-stranded DNA poses technical challenges due to its propensity to form hairpin structures. To solve this problem, the authors combine TIRF microscopy with optical tweezers to stretch the DNA and capture the dynamics of DNA unwinding by UvrD DNA helicase.
- Kyung Suk Lee
- , Hamza Balci
- & Taekjip Ha
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GATA simple sequence repeats function as enhancer blocker boundaries
GATA simple sequence repeats (SSRs) are located throughout vertebrate genomes in a non-random fashion. The authors show that these act as enhancer blocker elements in both human cells and Drosophila, indicating a conserved function of GATA SSRs.
- Ram P. Kumar
- , Jaya Krishnan
- & Rakesh K. Mishra
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| Open AccessSUMO2/3 modification of cyclin E contributes to the control of replication origin firing
The organized initiation of DNA replication at sites throughout the genome must be carefully choreographed to maintain genome stability. Bonne-Andrea and colleagues show that protein SUMOylation controls the density of origin firing, and identify cyclin E as an important substrate in this context.
- Catherine Bonne-Andrea
- , Malik Kahli
- & Olivier Coux
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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases
Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.
- Kyota Fujita
- , Yoko Nakamura
- & Hitoshi Okazawa
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| Open AccessGANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy
The affinity of antibodies for their targets is enhanced by somatic hypermutation, in which the cytidine deaminase AID is recruited to immunoglobulin variable region genes in B cells. Here the authors show that the nuclear protein GANP has an important role in this process by modifying chromatin structure and enhancing AID recruitment.
- Shailendra Kumar Singh
- , Kazuhiko Maeda
- & Nobuo Sakaguchi
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FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA
Internal modifications in mRNA and non-coding RNA are necessary for modulating various intracellular signalling pathways. In this study, the authors report novel modifications resulting from oxidative RNA demethylation, which regulate RNA–protein interactions affecting gene expression.
- Ye Fu
- , Guifang Jia
- & Chuan He
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Ribosomal protein S1 functions as a termination factor in RNA synthesis by Qβ phage replicase
Protein S1, a subunit of the Qß phage RNA-directed RNA polymerase, was thought to only initiate copying of the phage RNA plus strand. Here, the authors show that S1 stimulates replication of any cognate template by promoting release of the newly synthesized product strand.
- Nikita N. Vasilyev
- , Zarina S. Kutlubaeva
- & Alexander B. Chetverin
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Visualization and genetic modification of resident brain microglia using lentiviral vectors regulated by microRNA-9
Microglia are specialized immune cells in the brain. Here Åkerblom and colleagues use a microRNA-9-regulated lentiviral vector for the targeted genetic modification of microglia in the rodent brain, presenting a tool that may facilitate functional studies of resident microglia.
- Malin Åkerblom
- , Rohit Sachdeva
- & Johan Jakobsson
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| Open AccessmiR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit
Brown fat can dissipate energy as heat and has an important role in energy homoeostasis of rodents and possibly humans. Chenet al. show that microRNA 155 regulates the differentiation of brown adipocytes as well as the 'browning' of white fat cells in mice.
- Yong Chen
- , Franziska Siegel
- & Alexander Pfeifer
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A new protein complex promoting the assembly of Rad51 filaments
RecA/Rad51 proteins catalyse the recognition and exchange between two homologous DNA strands during homologous recombination. Sasanuma et al. now demonstrate that Rad51 association with ssDNA is mediated by a complex consisting of Psy3, Csm2, Shu1 and Shu2 proteins.
- Hiroyuki Sasanuma
- , Maki S. Tawaramoto
- & Akira Shinohara
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| Open AccessCSN- and CAND1-dependent remodelling of the budding yeast SCF complex
CAND1 promotes the activity of Cullin–RING ubiquitin ligases, but binds exclusively to inactive unneddylated forms of the enzyme. By identifying a simple means to reversibly activate this complex in budding yeast, Zemla et al. resolve this paradox and show that CAND1 acts as an exchange factor for substrate adaptors.
- Aleksandra Zemla
- , Yann Thomas
- & Thimo Kurz
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Impact of macromolecular crowding on DNA replication
Macromolecular crowding significantly affects interactions between macromolecules such as proteins, DNA and RNA. Akabayov and colleagues use a SAXS reconstitution assay to show that the effect of macromolecular crowding on T7 DNA replication causes structural changes of the replisome.
- Barak Akabayov
- , Sabine R. Akabayov
- & Charles C. Richardson
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| Open Accessβ-lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity
Sub-lethal concentrations of antibiotics are known to promote mutagenesis of bacterial DNA. Here the authors show that β-lactam antibiotics trigger mutagenesis by upregulating the stress-response protein RpoS, which downregulates mismatch-repair activity.
- A. Gutierrez
- , L. Laureti
- & I. Matic
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Structure of the full-length HCV IRES in solution
The hepatitis C virus RNA genome is translated via an internal ribosome entry site. Pérard et al. present an atomic model of this site, and using molecular dynamics simulations, identify conformational flexibility that may underlie its function during translation initiation.
- Julien Pérard
- , Cédric Leyrat
- & Marc Jamin
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A novel metatranscriptomic approach to identify gene expression dynamics during extracellular electron transfer
Extracellular electron transfer is a ubiquitous process that occurs in natural microbial communities. Here, Ishii et al.identify specific microbial strains and genes involved in extracellular electron transfer in a biofilm community that is associated with a microbial fuel cell.
- Shun’ichi Ishii
- , Shino Suzuki
- & Orianna Bretschger
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| Open AccessTopoisomerase IIα promotes activation of RNA polymerase I transcription by facilitating pre-initiation complex formation
Topoisomerases facilitate the progress of elongating polymerases during transcription. Zomerdijk and colleagues now demonstrate an additional role for this enzyme; their data suggest that Top2 can cleave DNA inducing topological changes at the ribosomal DNA promoter, which assists de novoassembly of the RNA polymerase I pre-initiation complex.
- Swagat Ray
- , Tatiana Panova
- & Joost C. B. M. Zomerdijk
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The role and assembly mechanism of nucleoprotein in influenza A virus ribonucleoprotein complexes
The nucleoprotein of negative-strand RNA viruses forms a part of the ribonucleoprotein complex. Here Turrell et al.show that nucleoprotein does not regulate the initiation and termination of transcription and replication by the viral RNA polymerase, suggesting that nucleoprotein instead is an elongation factor.
- Lauren Turrell
- , Jon W. Lyall
- & Frank T. Vreede
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Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations
Palindromic DNA sequences in the genome can cause gross chromosomal rearrangements. Inagaki et al.demonstrate how the pathways of Holliday-junction resolution and antigen-receptor gene rearrangement interact to process cruciform conformation of palindrome DNA into chromosomal translocations in human embryonic kidney cells.
- Hidehito Inagaki
- , Tamae Ohye
- & Hiroki Kurahashi
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MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency
Chromatin templates can act as barriers against cellular reprogramming. Gaspar-Maia and colleagues use mouse models deficient in the histone variants macroH2A1 and macroH2A2, and find that macroH2A functions as an epigenetic barrier against induced pluripotency by silencing Utx target genes.
- Alexandre Gaspar-Maia
- , Zulekha A. Qadeer
- & Emily Bernstein
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UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9
Epigenetic inheritance of DNA methylation requires the recruitment of DNA methyltransferase activity to the replication fork by UHRF1. Liu et al. show that optimal association of UHRF1 with the replication fork and resulting DNA methylation requires two domains that bind hemi-methylated DNA and methylated histones, respectively.
- Xiaoli Liu
- , Qinqin Gao
- & Jiemin Wong
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| Open AccessSir2a regulates rDNA transcription and multiplication rate in the human malaria parasite Plasmodium falciparum
The factors that modulate growth rate of the human malaria parasite Plasmodium falciparum remain poorly understood. Here Scherf and collaborators demonstrate that the Plasmodiumsirtuin PfSir2a regulates the transcription of ribosomal DNA, thereby modulating parasite proliferation rate and virulence.
- Liliana Mancio-Silva
- , Jose Juan Lopez-Rubio
- & Artur Scherf
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Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex
Expansion of CAG repeats in messenger RNAs is a common feature of various neurodegenerative disorders, including Huntington’s disease. Krauß et al.show that messenger RNAs with expanded CAG repeats bind to a protein complex that regulates translation and promotes overproduction of such aberrant proteins.
- Sybille Krauß
- , Nadine Griesche
- & Susann Schweiger
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DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes
Human cancer genomes often contain large amounts of single-nucleotide substitutions (SNS). Liu et al. catalogued SNS signatures across various cancer and normal genomes, demonstrating coordinative effects between replication timing and nuclear architecture on SNS patterns in cancer genomes.
- Lin Liu
- , Subhajyoti De
- & Franziska Michor
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A subset of Drosophila Myc sites remain associated with mitotic chromosomes colocalized with insulator proteins
Myc is a transcription factor present at gene promoters that activates expression of genes involved in pluripotency and cancer. Yang et al. report that Myc is also present at enhancers of Drosophilagenes during interphase and colocalizes with insulator proteins in mitosis.
- Jingping Yang
- , Elizabeth Sung
- & Victor G. Corces
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Strong bias in the bacterial CRISPR elements that confer immunity to phage
Bacterial CRISPR–Cas systems provide adaptive immunity against phage by transcribing interfering RNA from phage DNA inserted into the bacterial genome. Using deep-sequencing, the authors detect a bias in the phage genome locations sampled, suggestive of selection.
- David Paez-Espino
- , Wesley Morovic
- & Jillian F. Banfield
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FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress
DNA replication stress promotes genome instability and cell death. Here Fugger et al.describe how FBH1, via its helicase activity, is required to eliminate cells with excessive DNA replication stress, through the generation of MUS81-induced DNA double-strand breaks.
- Kasper Fugger
- , Wai Kit Chu
- & Claus Storgaard Sørensen
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Plant tumour biocontrol agent employs a tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase
Agrobacterium radiobacter strain K84 generates an antibiotic targeting pathogenic strains of Agrobacterium tumefaciens, enabling its use as a biocontrol to prevent infection of crops. Here the authors show that this antibiotic inhibits leucyl-tRNA synthetases via an unusual mechanism that depends on binding of tRNALeu.
- Shaileja Chopra
- , Andrés Palencia
- & John S. Reader
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Evolution of the protein stoichiometry in the L12 stalk of bacterial and organellar ribosomes
The ribosomal stalk L12 is the only multi-copy protein in the ribosome and is essential for translation. Here Davydov et al.use a bioinformatics and mass spectrometry approach to study the evolution of L12 in bacterial ribosomes and predict its stoichiometry in a wide range of species.
- Iakov I. Davydov
- , Ingo Wohlgemuth
- & Marina V. Rodnina
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MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11
The role of microRNAs in chemotherapy resistance remains to be elucidated. Bockhorn et al.report that microRNA-30c, a human breast tumour prognostic marker, has a key role by targeting the epithelial-to-mesenchymal transition promoter twinfilin 1 and downstream interleukin-11 expression.
- Jessica Bockhorn
- , Rachel Dalton
- & Huiping Liu
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