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Recombinant SINEs are formed at high frequency during induced retrotransposition in vivo
SINEs are retrotransposons that insert exact copies of themselves into genomes. Using a marked copy of a SINE, Yadavet al. show that the sequences of newly transposed SINEs are a combination of marked and existing SINEs, suggesting a mechanism for the formation of mosaic SINEs.
- Vijay Pal Yadav
- , Prabhat Kumar Mandal
- & Sudha Bhattacharya
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An atlas of DNA methylomes in porcine adipose and muscle tissues
Epigenetic and genetic factors have a role in obesity but the role of epigenetics in this disease is unclear. Here, Liet al. investigated global DNA methylation patterns in three breeds of pigs that have different fat contents, providing a resource for the further analysis of differentially methylated gene promoters in obesity.
- Mingzhou Li
- , Honglong Wu
- & Ruiqiang Li
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Article
| Open AccessSerine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition
Phosphorylation of the carboxy-terminal domain of RNA polymerase II is important for controlling gene transcription. In this study, the transcription elongation factor Tefb is shown to phosphorylate serine-5 and its activity is enhanced when the polymerase is already phosphorylated on serine-7.
- Nadine Czudnochowski
- , Christian A. Bösken
- & Matthias Geyer
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A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response
The bone morphogenetic protein (BMP) and Smad1 signalling pathway is required for embryogenesis. In this study, Smad1 is shown to be phosphorylated by Atm in response to DNA damage and this results in elevated Smad1 signalling, thus uncovering a new role for this pathway in the DNA damage response.
- Jenny Fung Ling Chau
- , Deyong Jia
- & Baojie Li
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Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression
Tumour cells are subject to replication stress but how cells overcome damage without inducing senescence and apoptotic pathways is unclear. Here, the authors study polyploidy in cancer cells and show that this blocks apoptotic and senescent pathways, resulting in the induction of proteins involved in DNA repair.
- Li Zheng
- , Huifang Dai
- & Binghui Shen
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Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster
Hox gene expression is induced upon cellular differentiation and is inhibited in pluripotent cells. Bocker and colleagues show that the maintenance of induced transcription depends on Tet2 mediated hydroxylation of 5-methylcytosine at theHoxagene locus, indicating that this epigenetic switch is required for an active chromatin state and gene expression.
- Michael T. Bocker
- , Francesca Tuorto
- & Achim Breiling
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Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila
Adars are adenosine deaminases that act on RNAs, including those encoding proteins involved in neuronal transmission and also Adar RNA. Here, Savvaet al. engineered knock-in Drosophila mutants with altered Adar autoediting and found that this changed the spectrum of adenosine deamination and Drosophilabehaviour.
- Yiannis A. Savva
- , James E.C Jepson
- & Robert A. Reenan
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The structure of the FANCM–MHF complex reveals physical features for functional assembly
Fanconi's anaemia is characterized by an inability to repair DNA damage and is associated with mutations in the Fanconi anaemia nuclear complex, which includes the protein FANCM. This study reports the crystal structures of a fragment of FANCM bound to the histone-fold-containing protein complex, MHF1–MHF2.
- Yuyong Tao
- , Changjiang Jin
- & Maikun Teng
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miR-484 regulates mitochondrial network through targeting Fis1
Abnormal mitochondrial fission leads to apoptosis and disease. Li and colleagues reveal the mechanism with which the transcription factor Foxo3a suppresses Fis1-mediated mitochondrial fission and apoptosis in cardiomyocytes and adrenocortical cancer cells, which involves miR-484 inhibition of Fis1 translation.
- Kun Wang
- , Bo Long
- & Pei-Feng Li
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The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies
The C terminus of TAR DNA-binding protein 43 (TDP-43) forms aggregates that are a feature of some neurodegenerative diseases. In this study, Changet al.show that C terminus of TDP-43 interacts with itself, altering its cellular localisation and the splicing function of the protein.
- I.-Fan Wang
- , Hsiang-Yu Chang
- & C.-K. James Shen
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Article
| Open AccessFAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure
Lysine-specific demethylase 1 (LSD1) removes methyl groups from mono-methylated and dimethylated lysine 4 of histone H3 and represses transcription. In this study, a role for LSD1 in the regulation of genes involved in energy expenditure in adipocytes is reportedin vitroand in mice fed on a high-fat diet.
- Shinjiro Hino
- , Akihisa Sakamoto
- & Mitsuyoshi Nakao
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| Open AccessSUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair
Tyrosyl DNA phosphodiesterase 1 (TDP1) repairs DNA breaks and is mutated in the disease Spinocerebellar Ataxia with Axonal Neuropathy. Here TDP1 is shown to be post-translationally modified by sumoylation of lysine 111, and cells carrying a mutation at this residue are inefficient at single-strand DNA break repair.
- Jessica J.R. Hudson
- , Shih-Chieh Chiang
- & Sherif F. El-Khamisy
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Multiple exposures to drought 'train' transcriptional responses in Arabidopsis
Whether plants can remember their transcriptional response to stress is unknown. By repeatedly exposingArabidopsisto drought, we show that the plants remember their transcriptional response to stress and that the altered genes retain the epigenetic mark H3K4me3 and stalled phosphorylated polymerase II.
- Yong Ding
- , Michael Fromm
- & Zoya Avramova
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RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization
Megakaryocytes undergo polyploidization prior to forming platelets but this process is poorly characterised. In this study, non-muscle myosin IIB heavy chain, that localizes to the contractile ring during mitosis, is shown to be silenced prior to polyploidization in a RUNX1-dependent manner.
- Larissa Lordier
- , Dominique Bluteau
- & Yunhua Chang
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The tRNA methyltransferase NSun2 stabilizes p16INK4 mRNA by methylating the 3′-untranslated region of p16
The expression of the tumour suppressor p16 is frequently lost in cancer. Zhanget al. show in cultured cells that p16 mRNA levels are stabilised by methylation of the 3′-untranslated region by the tRNA methyltransferase NSun2, revealing a new mechanism for regulating p16.
- Xiaotian Zhang
- , Zhenyun Liu
- & Wengong Wang
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| Open AccessTelomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence
Irreparable DNA damage leads to apoptosis or senescence. Hewittet al. show that, in response to genotoxic or oxidative stress, DNA damage occurs predominantly at telomere associated foci, which accumulate with age in vivo, irrespective of telomerase activity.
- Graeme Hewitt
- , Diana Jurk
- & João F. Passos
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miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia
HOX9AandMEIS1are key oncogenes in MLL-rearranged leukaemia. miRNA-196b is shown here to directly suppress their expression and delay MLL-fusion-mediated leukaemia, but to also cause an aggressive leukaemia phenotype when expressed ectopically, suggesting that it targets tumour suppressors as well.
- Zejuan Li
- , Hao Huang
- & Jianjun Chen
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Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
PADI4 is an enzyme that converts arginine residues to citrulline. Here, Tanikawa and colleagues show that, in response to DNA damage, histone H4 and Lamin C are citrullinated in a p53 and PADI4-dependent manner andPadi4-dependent manner and Padi4 null mice are resistant to radiation-induced apoptosis in the thymus.
- Chizu Tanikawa
- , Martha Espinosa
- & Koichi Matsuda
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| Open AccessABL1 regulates spindle orientation in adherent cells and mammalian skin
A systematic approach for identifying the genes responsible for the regulation of spindle orientation in mammals has been lacking. Now, Matsumuraet al. perform a kinase-targeting RNAi screen and identify ABL1, which through the direct phosphorylation of NuMa, is a novel regulator of spindle orientation.
- Shigeru Matsumura
- , Mayumi Hamasaki
- & Fumiko Toyoshima
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| Open AccessELL facilitates RNA polymerase II pause site entry and release
The super elongation complex, which is involved in transcriptional elongation, contains the Eleven-nineteen Lysine-rich Leukemia protein (ELL). In this study, ELL is shown to stabilize RNA polymerase II prior to recruitment into the super elongation complex, suggesting ELL has a role in early transcription elongation.
- Jung S. Byun
- , Temesgen D. Fufa
- & Kevin Gardner
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| Open AccessStructure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor
Albumin transport proteins circulate in the blood and are protected from degradation by interaction with the neonatal Fc receptor. Andersenet al. investigate the albumin binding site of the neonatal Fc receptor and find pH sensitive ionic networks at the binding interface.
- Jan Terje Andersen
- , Bjørn Dalhus
- & Inger Sandlie
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| Open AccessBRCA1 is an essential regulator of heart function and survival following myocardial infarction
The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer. Now, Shuklaet al.demonstrate that mice lacking BRCA1 in cardiomyocytes are more sensitive to ischaemia than control mice, and that BRCA1 is elevated in human tissues exposed to ischaemia, suggesting a cardioprotective role for BRCA1.
- Praphulla C. Shukla
- , Krishna K. Singh
- & Subodh Verma
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Specific inhibition of bacterial RNase T2 by helix 41 of 16S ribosomal RNA
The 30S ribosomal subunit ofEscherichia coliinhibits the RNA-degrading enzyme Ribonuclease T2. Using mutational studies and hybrid ribosomes, Kitahara and Miyazaki show that helix 41 of the 30S ribosomal subunit blocks the enzyme activity, suggesting that helix 41 is required for preventing RNase T2 toxicity.
- Kei Kitahara
- & Kentaro Miyazaki
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| Open AccessGenome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis
microRNAs are known to be deregulated in cancer. Using a screen for microRNAs that alter cell migration, Zhanget al. show that mir-23b blocks cell migration in vitro and in vivoand is reduced in expression in human colon cancer, suggesting a therapeutic potential for this microRNA.
- Hanshuo Zhang
- , Yang Hao
- & Jianzhong Jeff Xi
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Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway
Cell fusion is involved in many different cellular processes including the fusion of trophoblast cells in the placenta. Matsuuraet al. identify a role for the β-catenin signalling pathway in the regulation of the transcription factor GCM1 and therefore the fusion of syncytiotrophoblast cells.
- Ken Matsuura
- , Takafumi Jigami
- & Tetsu Akiyama
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MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a
The methylation of DNA and histone H3 lysine 9 in chromatin are positively correlated. This study shows that the DNA methyl transferase Dnmt3a is methylated, and a crystal structure of Dnmt3a bound to the chromodomain protein MPP8 suggests a molecular mechanism.
- Yanqi Chang
- , Lidong Sun
- & Xiaodong Cheng
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miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells
The microRNA miR-137 is enriched in the brain of mice and induces the differentiation of adult neural stem cells. Now, Sun and colleagues report that miR-137 negatively regulates proliferation of neurons in embryonic mice and that TLX and LSD1 cooperate to negatively regulate miR-137 expression, blocking premature differentiation.
- GuoQiang Sun
- , Peng Ye
- & Yanhong Shi
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Article
| Open AccessSelective inhibition of microRNA accessibility by RBM38 is required for p53 activity
MicroRNAs bind to the 3′-untranslated region of genes to regulate expression. In this study, an RNA-binding protein, RMB38, is shown to selectively regulate the access of some microRNAs to their targets, and control the expression of some p53 target genes.
- Nicolas Léveillé
- , Ran Elkon
- & Reuven Agami
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The ubiquitin ligase HACE1 regulates Golgi membrane dynamics during the cell cycle
The Golgi membrane is fragmented during mitosis and is subsequently fused following cell division and this process is known to be controlled by ubiquitination. In this study, the ubiquitin ligase HACE1 is shown to be targeted to the Golgi membrane and is required for fusion after the completion of mitosis.
- Danming Tang
- , Yi Xiang
- & Yanzhuang Wang
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Article
| Open AccessA shift of the TOR adaptor from Rictor towards Raptor by semaphorin in C. elegans
What controls the binding partner selection of the target of rapamycin protein, TOR, is unknown. Using theCaenorhabditis elegans tail as a model, Nukazuka et al. determine that signals of semaphorin through plexin control the binding partner selection of TOR and are required for the correct organization of rays in the tail.
- Akira Nukazuka
- , Shusaku Tamaki
- & Shin Takagi
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p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression
Cellular senescence is characterized by the cessation of cell growth and the expression of the p16 protein. In this study, inhibition or loss of p300, a histone acetyltransferase, is shown to result in senescence that occurs independently of p16 and is associated with histone hypoacetylation and altered replication timing.
- Alexandre Prieur
- , Emilie Besnard
- & Jean-Marc Lemaitre
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Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling
Transforming growth factor-β blocks the activation of pro-inflammatory cytokines, in part by the degradation of Myd88. This study shows that smad ubiquitin regulator proteins are shown to mediate the destruction of Myd8 and are therefore required for the anti-inflammatory effects of transforming growth factor-β.
- Youn Sook Lee
- , Jin Seok Park
- & Seok Hee Park
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Article
| Open AccessA segmental genomic duplication generates a functional intron
The appearance of a new intron that splits an exon without disrupting the corresponding peptide sequence is a rare event in vertebrate genomes. Hellstenet al.demonstrate that, under certain circumstances, a functional intron can be produced in a single step by segmental genomic duplication.
- Uffe Hellsten
- , Julie L. Aspden
- & Daniel S. Rokhsar
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SIRT6 is required for maintenance of telomere position effect in human cells
Chromatin is rendered silent by epigenetic marks when in proximity to telomeres, and, in yeast, this effect requires the histone-modifying enzyme Sir2. In this study, the human Sir2 family member SIRT6 is shown to modulate the telomere position effect in human cells.
- Ruth I. Tennen
- , Dennis J. Bua
- & Katrin F. Chua
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Article
| Open AccessEditing of human KV1.1 channel mRNAs disrupts binding of the N-terminus tip at the intracellular cavity
RNA editing is important in regulating neuronal excitability, and a specific editing event has been shown to alter the permeation pathway of voltage-gate potassium channels. Gonzalezet al.find that the tip of the channel's inactivation gate makes a direct hydrophobic interaction with the edited position.
- Carlos Gonzalez
- , Angelica Lopez-Rodriguez
- & Miguel Holmgren
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Article
| Open AccessCytosine methylation regulates oviposition in the pathogenic blood fluke Schistosoma mansoni
The chronic disease schistosomiasis is caused by the blood flukeSchistosoma mansoni. By studying DNA modifications throughout the lifecycle of the pathogen, the authors identify DNA methylation as a factor in egg development and suggest that the epigenetic machinery responsible may be a therapeutic target.
- Kathrin K. Geyer
- , Carlos M. Rodríguez López
- & Karl F. Hoffmann
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Regulation of MITF stability by the USP13 deubiquitinase
MITF is a transcription factor required for melanocyte development, which is activated in some melanomas. Zhao and colleagues show that USP13 removes ubiquitin from MITF, stabilizes MITF protein levels and enhances colony formation, suggesting that USP13 may be a therapeutic target in melanoma.
- Xiansi Zhao
- , Brian Fiske
- & David E Fisher
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Article
| Open AccessToxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells
Polo-like kinase 1 is a key regulator of mitosis and is a candidate for drug development to treat cancer. Here, reduced expression of polo-like kinase 1 in adult mice has a minor impact on animal physiology, suggesting that polo-like kinase 1 inhibitors may be useful in the killing of tumour cells while sparing normal cells.
- Monika Raab
- , Sven Kappel
- & Klaus Strebhardt
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Article
| Open AccessArabidopsis nitrate reductase activity is stimulated by the E3 SUMO ligase AtSIZ1
Posttranslational modification of proteins by small ubiquitin-related modifier is a response to stress signalling in plants. Here, theArabdiposisprotein SIZ1 is shown to cause SUMOylation of nitrate reductases 1 and 2 and to increase their activity, suggesting that SIZ1 controls nitrate uptake via SUMOylation.
- Bong Soo Park
- , Jong Tae Song
- & Hak Soo Seo
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Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome
Mutations in the DNA helicaseBLM cause Bloom syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLMare shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.
- Pauline Chabosseau
- , Géraldine Buhagiar-Labarchède
- & Mounira Amor-Guéret
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Cyclin B-dependent kinase 1 regulates human TRF1 to modulate the resolution of sister telomeres
TRF1 is a telomere binding protein involved in sister telomere cohesion. In this study, the ability of TRF1 to bind to telomeres in mitosis is inhibited by cyclin-dependent kinase 1-mediated phosphorylation, which may facilitate sister telomere resolution during mitosis.
- Megan McKerlie
- & Xu-Dong Zhu
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MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma
α-fetoprotein is used as a biomarker of hepatocellular cancer but the mechanisms that lead to its elevated expression are unknown. Kojimaet al.show that microRNA122 and CUX1 are important for the regulation of α-fetoprotein and suggest that loss of microRNA122 leads to more aggressive liver cancer.
- Kentaro Kojima
- , Akemi Takata
- & Kazuhiko Koike
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Potential for interdependent development of tRNA determinants for aminoacylation and ribosome decoding
Aminoacyl-transfer RNA synthetases are conserved between bacteria and eukaryotes; however, bacterial enzymes cannot acylate eukaryote tRNAs. Now, fusion of a human and bacterial enzyme is shown to overcome the species barrier and confer tRNA specificity during both codon selection and proofreading on the ribosome.
- Cuiping Liu
- , Howard Gamper
- & Ya-Ming Hou
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Article
| Open AccessTRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer
TGFβ can function as both a tumour suppressor and tumour promoter under different cellular contexts. Here, the cleavage product of the TGFβ type I receptor is shown to be generated in a TGFβ-dependent manner, and can induce the expression of genes involved in tumour cell invasion.
- Yabing Mu
- , Reshma Sundar
- & Marene Landström
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Article
| Open AccessIntron retention in the Drosophila melanogaster Rieske iron sulphur protein gene generated a new protein
Genomes evolve with time but the molecular mechanisms that underlie this process are poorly understood. Gontijoet al. describe a protein that was generated by the retention of an intron in the Drosophila melanogaster Rieske iron sulphur proteingene and show that the resulting protein is translated.
- Alisson M. Gontijo
- , Veronica Miguela
- & Maria Dominguez
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Article
| Open AccessStructure and Scm3-mediated assembly of budding yeast centromeric nucleosomes
There is debate about the structural organization of the yeast centromeric nucleosome and the role of the nonhistone protein Scm3 in its assembly. Dechassaet al.find that yeast centromeric nucleosomes organize DNA in a left-handed superhelix, and show that Scm3 is a specific nucleosome assembly factor.
- Mekonnen Lemma Dechassa
- , Katharina Wyns
- & Karolin Luger
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Article
| Open AccessPredicting sites of ADAR editing in double-stranded RNA
ADAR enzymes edit double-stranded RNA, converting adenosines to inosines, and are essential for neuronal function. Eggingtonet al. quantify edit sites in RNA using a Sanger sequencing protocol and use the resulting data to develop algorithms to predict RNA edit sites.
- Julie M. Eggington
- , Tom Greene
- & Brenda L. Bass
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Article
| Open AccessIKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways
IKK kinases activate nuclear factor-κB, and the activated form of this transcription factor is found in endothelial cells in diseased tissue. In this study, mice lacking IKKβ in the endothelium are generated, and it is shown that defects in endothelial cell function are both IKK kinase activity dependent and independent.
- Noboru Ashida
- , Sucharita SenBanerjee
- & Anthony Rosenzweig
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Article
| Open AccessChemical treatment enhances skipping of a mutated exon in the dystrophin gene
Duchenne muscular dystrophy is caused by a loss of thedystrophin gene, and control of dystrophin mRNA splicing could aid treatment of the disease. Nishida et al. show that a small molecule promotes skipping of exon 31 and increases production of a functional dystrophin protein in a patient.
- Atsushi Nishida
- , Naoyuki Kataoka
- & Masafumi Matsuo
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