Featured
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HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA
The nuclear protein HMGB1 is involved in muscle fibre formation. Here, Dormoy-Raclet et al. show that during muscle cell differentiation, the RNA-binding protein HuR promotes HMGB1mRNA translation by preventing its repression by miR-1192.
- Virginie Dormoy-Raclet
- , Anne Cammas
- & Imed-Eddine Gallouzi
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| Open AccessHuman DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs
Agents that cause DNA interstrand crosslinks are widely used to treat cancer. Takata et al.show that the DNA helicase HELQ associates with ATR and RAD51 paralogs, which are components of DNA repair pathways, and helps defend human cells against agents that induce DNA interstrand crosslinks.
- Kei-ichi Takata
- , Shelley Reh
- & Richard D. Wood
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| Open AccessA versatile cis-acting inverter module for synthetic translational switches
Artificial genetic circuits have been designed to enable precise control of cellular behaviour and phenotypes. Saito and colleagues present a new RNA module that can invert the function of a translational OFF to an ON switch and demonstrate its utility in mammalian cells.
- Kei Endo
- , Karin Hayashi
- & Hirohide Saito
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An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms
Protein deacetylases of the sirtuin family have important roles in aging and metabolism. Using peptide microarrays displaying physiological lysine acetylation sites, the authors map the substrate preferences of all seven human sirtuin isoforms, revealing enzyme specificities and identifying new sirtuin substrates.
- David Rauh
- , Frank Fischer
- & Clemens Steegborn
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BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids
Absence of Brca2 or Rad51 paralogues biases homologous recombination towards the error-prone outcome of long-tract gene conversion. Here, the authors report that BRCA1, together with the end resection protein CtIP, controls the balance between short- and long-tract gene conversion, thereby affecting the fidelity of homologous recombination.
- Gurushankar Chandramouly
- , Amy Kwok
- & Ralph Scully
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| Open AccessWall teichoic acid structure governs horizontal gene transfer between major bacterial pathogens
Horizontal gene transfer of mobile genetic elements contributes to bacterial evolution and emergence of new pathogens. Here the authors demonstrate that the highly diverse structure of wall teichoic acid polymers governs horizontal gene transfer among Gram-positive pathogens, even across long phylogenetic distances.
- Volker Winstel
- , Chunguang Liang
- & Guoqing Xia
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Article
| Open AccessATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy
The protein ATG5 is known to be involved in the formation of autophagosomes. Here, Maskey et al. identify a new role of ATG5 in response to drug-induced DNA damage whereby ATG5 translocates to the nucleus, leading to chromosome misalignment and mitotic catastrophe.
- Dipak Maskey
- , Shida Yousefi
- & Hans-Uwe Simon
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Mechanism for full-length RNA processing of Arabidopsis genes containing intragenic heterochromatin
Transposable elements found within transcribed regions of genes are often compacted into heterochromatin. Using Arabidopsisas a model, these authors show that the protein, IBM2, is required for correct processing of genes that contain intragenic heterochromatin.
- Hidetoshi Saze
- , Junko Kitayama
- & Tetsuji Kakutani
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| Open AccessEndonuclease V cleaves at inosines in RNA
Bacterial endonuclease V enzymes are characterized as DNA repair proteins. Here the authors show that human endonuclease V is an inosine-specific ribonuclease, indicating a role for this enzyme in normal RNA metabolism rather than DNA repair.
- Erik Sebastian Vik
- , Meh Sameen Nawaz
- & Ingrun Alseth
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| Open AccessHuman endonuclease V is a ribonuclease specific for inosine-containing RNA
In Escherichia coli, the highly conserved enzyme endonuclease V has a role in DNA repair. Here the authors show that human endonuclease V is an inosine 3' endoribonuclease and that Tudor Staphylococcal nuclease enhances this activity, suggesting a role for human endonuclease V in RNA metabolism.
- Yoko Morita
- , Toshihiro Shibutani
- & Isao Kuraoka
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PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine
Tet proteins control DNA demethylation, but how the DNA target regions are determined is unclear. Here the authors report that during adipocyte differentiation, PPARγ binds to the PPAR-response element and recruits Tet proteins, thereby inducing local DNA demethylation.
- Katsunori Fujiki
- , Akihiro Shinoda
- & Masayuki Murata
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Dissecting the role of H3K64me3 in mouse pericentromeric heterochromatin
H3K64 trimethylation on the nucleosome lateral surface marks pericentric heterochromatin. Here Lange et al.show that H3K64me3 enrichment ensures heterochromatin integrity and occurs in an H3K9me3-dependent, but an H4K20me3- and heterochromatin protein 1-independent manner.
- Ulrike C. Lange
- , Stéphanie Siebert
- & Robert Schneider
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Tertiary structural elements determine the extent and specificity of messenger RNA editing
A central, imperfect duplex RNA secondary structure is generally required for site-specific adenosine-to-inosine RNA editing by ADAR enzymes. Rieder et al. show in Drosophila that conserved and complex long-range RNA tertiary structures form in vivoand can also regulate specific RNA-editing events by ADAR enzymes.
- Leila E. Rieder
- , Cynthia J. Staber
- & Robert A. Reenan
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Genome-wide search for exonic variants affecting translational efficiency
Genetic effects on gene expression by variants at expression quantitative trait loci (eQTLs), can contribute to human genetic diseases. Here, Liet al. present a method to study eQTLs with effects on protein translation on a transcriptome-wide scale.
- Quan Li
- , Angeliki Makri
- & Hui-Qi Qu
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The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage
Mice lacking the C-terminal non-core domain of RAG2 and ATM mutant mice develop thymic lymphomas harbouring recurrentTcra/d–Ightranslocations. Here the authors show that ATM and the non-core domain of RAG2 prevent bi-locus recombination by modulating higher-order chromatin structure.
- Julie Chaumeil
- , Mariann Micsinai
- & Jane A. Skok
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The effects of carbon dioxide and temperature on microRNA expression in Arabidopsis development
An increase in the concentration of atmospheric carbon dioxide and warmer temperatures can alter plant growth and development. Here the authors show that these conditions can also elicit significant changes in microRNAs expression, including some which might induce early flowering in Arabidopsis.
- Patrick May
- , Will Liao
- & Qiong A. Liu
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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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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