Featured
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Research Highlights |
Genetics: Long and the short of it
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Letter |
Production of p53 gene knockout rats by homologous recombination in embryonic stem cells
The rat is a animal model widely used for studying human physiology and disease, but functional genomics and genetic research have been stifled by the limited availability of gene targeting tools. These authors have established gene targeting by homologous recombination in rat embryonic stem cells, and have generated p53 gene knockout rats for the first time.
- Chang Tong
- , Ping Li
- & Qi-Long Ying
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Letter |
OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma
One model for cancer development posits that the proliferating cells in a tumour can become 'addicted' to activating mutations in an oncogene. With the realization that certain microRNAs promote tumorigenesis, it has been proposed that tumours may also become dependent on such 'oncomiRs'. Here, evidence is provided that the gene encoding microRNA-21 is an oncogene, and that in its absence, tumours undergo apoptosis and regress. Thus tumours can indeed become addicted to oncomiRs.
- Pedro P. Medina
- , Mona Nolde
- & Frank J. Slack
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Letter |
Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells
The ability of retrotransposons to mobilize and insert into genes presents a challenge to a cell needing to maintain its genomic integrity. These authors have studied retrotransposition in embryonic carcinoma-derived cells. On insertion into DNA, the retrotransposon is quickly silenced, but the retrotransposon-specificity of this process implies that multiple silencing mechanisms may exist. Once cells differentiate, the ability to silence newly introduced retrotransposons is lost but previously inactivated retrotransposons remain inactive.
- Jose L. Garcia-Perez
- , Maria Morell
- & John V. Moran
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Research Highlights |
Cancer biology: Blood vessel regulator
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Letter |
A ribosome-associating factor chaperones tail-anchored membrane proteins
Tail-anchored proteins have a single transmembrane domain at their carboxy termini and are post-translationally targeted to the endoplasmic reticulum via the cytosolic ATPase TRC40. These authors identify a conserved protein complex called Bat3 complex that is recruited to ribosomes, interacts with the transmembrane domain of newly released tail-anchored proteins and transfers them to TRC40 for subsequent targeting to the endoplasmic reticulum.
- Malaiyalam Mariappan
- , Xingzhe Li
- & Ramanujan S. Hegde
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Letter |
New class of gene-termini-associated human RNAs suggests a novel RNA copying mechanism
In the course of characterizing short RNAs from human cells using single-molecule high-throughput sequencing, these authors identify a new short RNA species. The presence of non-genomically encoded poly(U) residues at their 5' ends implies the existence of an unknown RNA copying mechanism in human cells.
- Philipp Kapranov
- , Fatih Ozsolak
- & Patrice M. Milos
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Letter |
Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression
LRRK2 activity is dysregulated in Parkinson's disease, but how it contributes to the pathogenesis is unknown. These authors show that Drosophila LRRK2 interacts with the Argonaute component (dAgo1) of the RNA-induced silencing complex. This is associated with reduced levels of dAgo1, interaction between phospho-4E-BP1 and hAgo2, and impairment of microRNA-mediated repression. This leads to overexpression of the cell cycle genes e2f1 and dp, and consequent degeneration of dopaminergic neurons.
- Stephan Gehrke
- , Yuzuru Imai
- & Bingwei Lu
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News |
Mystery RNA spawns gene-activating peptides
Short peptides that regulate fruitfly development are produced from 'junk' RNA.
- Heidi Ledford
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Article |
Ribosome dynamics and tRNA movement by time-resolved electron cryomicroscopy
During protein synthesis within the ribosome, transfer RNAs (tRNAs) move sequentially through different sites as their attached amino acids are transferred onto the growing protein chain. Large conformational movements accompany this process. Here, a staggering 1.9 million electron cryomicroscopy images of the ribosome have been processed to visualize these changes. The results reveal that the ribosome functions as a Brownian machine that couples spontaneous changes driven by thermal energy to directed movement.
- Niels Fischer
- , Andrey L. Konevega
- & Holger Stark
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News & Views |
Translocation in slow motion
Time-resolved electron microscopy can capture structural changes in active macromolecular complexes, but detailed imaging is essential. The dynamics of one step in protein synthesis has been deduced from two million images.
- Måns Ehrenberg
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Letter |
Regulation of heterochromatic DNA replication by histone H3 lysine 27 methyltransferases
DNA replication occurs only once per cell cycle, and numerous pathways prevent re-replication. Here it is shown that mutations in ARABIDOPSIS TRITHORAX-RELATED PROTEIN5 (ATXR5) and ATXR6 — which encode histone methyltransferases — lead to re-replication of specific genomic locations, notably those corresponding to transposons and other repetitive and silenced elements. ATXR5 and ATXR6 are proposed to be components of a pathway that prevents over-replication of heterochromatin in Arabidopsis.
- Yannick Jacob
- , Hume Stroud
- & Steven E. Jacobsen
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Letter |
A novel pathway regulates memory and plasticity via SIRT1 and miR-134
The deacetylase SIRT1 has been suggested to function in normal brain physiology, but it is not known whether it participates in higher-order brain functions. These authors demonstrate a role for SIRT1 in synaptic plasticity and memory formation, with activation enhancing synaptic strength and memory formation. These effects were regulated through a post-transcriptional mechanism involving CREB activation and miR-134 production. This interplay represents another mechanism of plasticity regulation with behavioural consequences.
- Jun Gao
- , Wen-Yuan Wang
- & Li-Huei Tsai
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Letter |
PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression
These authors show that the JmjC domain-containing protein PHF8 has histone demethylase activity against H4K20me1 and is linked to two distinct events during cell cycle progression. PHF8 is recruited to the promoters of genes involved in the G1–S phase transition, where it removes H4K20me1 and contributes to gene activation, whereas dissociation of PHF8 from chromatin in prophase allows H4K20me1 to accumulate during mitosis.
- Wen Liu
- , Bogdan Tanasa
- & Michael G. Rosenfeld
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Letter |
Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition
Birds and mammals have distinct sex chromosomes: in birds, males are ZZ and females ZW; in mammals, males are XY and females XX. By sequencing the chicken Z chromosome and comparing it with the human X chromosome, these authors overturn the currently held view that these chromosomes have diverged little from their autosomal progenitors. The Z and X chromosomes seem to have followed convergent evolutionary trajectories, despite evolving with opposite systems of heterogamety.
- Daniel W. Bellott
- , Helen Skaletsky
- & David C. Page
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Letter |
Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b
The lysine residues of histone proteins can be acetylated or methylated, with important effects on gene expression. Until recently the protein modules that bind acetyl-lysine have been limited to bromodomains. However, the tandem plant homeodomain (PHD) finger of human DPF3b — which is involved in gene activation — has also been reported to bind to acetylated histones. Here, three-dimensional solution structures of DPF3b offer mechanistic insight into how this protein recognizes acetylation marks.
- Lei Zeng
- , Qiang Zhang
- & Ming-Ming Zhou
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Letter |
Conserved role of intragenic DNA methylation in regulating alternative promoters
The methylation of DNA in 5′ promoter regions suppresses gene expression, but what is the role of DNA methylation in the bodies of genes? Here, a map of DNA methylation is generated from human brain tissue; it is found that most methylated CpG islands are within intragenic and intergenic regions, rather than within promoters. It is proposed that intragenic methylation regulates the expression of alternative gene transcripts in different tissues and cell types.
- Alika K. Maunakea
- , Raman P. Nagarajan
- & Joseph F. Costello
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Article |
Striatal microRNA controls cocaine intake through CREB signalling
Extended cocaine taking triggers several structural and functional changes in the brain that may lead to compulsive drug seeking, but the mechanisms that regulate the process are unclear. Here, a microRNA — miR-212 — is identified that is upregulated in the striatum of rats with a history of extended access to cocaine. The authors suggest that miR-212 protects against the development of compulsive drug taking, and that it may act through the CREB protein, a known regulator of the rewarding effects of cocaine.
- Jonathan A. Hollander
- , Heh-In Im
- & Paul J. Kenny
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News & Views |
MicroRNA knocks down cocaine
Cocaine abuse results in increased craving for the drug. But in the long run, cocaine intake induces the expression of a microRNA in the brain, and this seems to limit further drug intake.
- Marina R. Picciotto
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Letter |
Subnanometre single-molecule localization, registration and distance measurements
These authors have developed a method that enables them to observe single-molecule fluorescent probes with subnanometre precision and accuracy using conventional far-field fluorescence imaging. The improved resolution will enable researchers to characterize single 'molecules' of large, multisubunit biological complexes in biologically relevant environments.
- Alexandros Pertsinidis
- , Yunxiang Zhang
- & Steven Chu
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Letter |
SCFCyclin F controls centrosome homeostasis and mitotic fidelity through CP110 degradation
Cyclin F is the founding member of the F-box protein family but its functions are unknown; unlike most cyclins, it does not bind or activate cyclin-dependent kinases. Here the authors identify CP110, a protein essential for centrosome duplication, as a substrate of Cyclin F. CP110 and Cyclin F associate on centrioles during the cell cycle, and Cyclin F is proposed to limit centrosome duplication by targeting CP110 for degradation.
- Vincenzo D’Angiolella
- , Valerio Donato
- & Michele Pagano
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Article |
Chromatin regulation by Brg1 underlies heart muscle development and disease
Cardiac hypertrophy is associated with a decrease in expression of the adult isoform of the molecular motor myosin heavy chain (α-MHC) and the induction of expression of its fetal isoform (β-MHC). Here the authors reveal the mechanism regulating this switch in expression, which impairs heart function. Cardiac stress in adult hearts reactivates the developmental chromatin-modifying complex Brg1/BAF, which interacts with histone deacetylase and poly (ADP ribose) polymerase to induce a pathological α-MHC-to-β-MHC shift.
- Calvin T. Hang
- , Jin Yang
- & Ching-Pin Chang
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Letter |
The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor
Although pheromones and their detection by the vomeronasal organ are known to govern social behaviour in mice, specific chemical signals have rarely been linked to selective behavioural responses. Here the authors show that the ESP1 peptide secreted in male tears makes females sexually receptive, and identify its specific vomeronasal receptor and the sex-specific neuronal circuits activated during the behavioural response.
- Sachiko Haga
- , Tatsuya Hattori
- & Kazushige Touhara
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Letter |
Single-cell NF-κB dynamics reveal digital activation and analogue information processing
Multicellular organisms, particularly their immune systems, rely on complex cell-to-cell communication, mediated by signalling molecules that form spatiotemporal concentration gradients. Here, high-throughput microfluidic cell culture and fluorescence microscopy, together with quantitative gene expression analysis and mathematical modelling, have been used to investigate how mammalian cells respond to different levels of TNF-α and signal to NF-κB. Both digital and analogue responses are revealed.
- Savaş Tay
- , Jacob J. Hughey
- & Markus W. Covert
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Letter |
Activation of autophagy during cell death requires the engulfment receptor Draper
- Christina K. McPhee
- , Mary A. Logan
- & Eric H. Baehrecke
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Article |
Structure and mechanism of human DNA polymerase η
Ultraviolet radiation causes damage to DNA in skin cells, blocking DNA replication and causing mutations that can lead to cancer. One way in which the cell deals with such damage involves specialized DNA polymerases, such as Polη, that can bypass lesions. Here the crystal structure of Polη is presented at four consecutive steps during DNA synthesis through thymine dimers. Polη acts like a 'molecular splint' to stabilize damaged DNA, and accommodates the thymine dimer in an atypically large active site.
- Christian Biertümpfel
- , Ye Zhao
- & Wei Yang
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Letter |
Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
Engagement of the tumour-necrosis factor (TNF) receptor results in the assembly of multi-component signalling complexes by adaptor proteins that include TNF receptor-associated factor 2 (TRAF2). Genetic evidence indicates that TRAF2 is needed for the polyubiquitination of receptor interacting protein 1 (RIP1), but direct evidence has been lacking. Here it is shown that the lipid sphingosine-1-phosphate is a co-factor needed for this ubiquitination activity of TRAF2.
- Sergio E. Alvarez
- , Kuzhuvelil B. Harikumar
- & Sarah Spiegel
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Article |
A coding-independent function of gene and pseudogene mRNAs regulates tumour biology
The canonical role of messenger RNA (mRNA) is in protein coding and synthesis. But could mRNAs also have a role that is related to their ability to compete for microRNA binding? Here, the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 is investigated. The results suggest that pseudogenes have a biological function, in sequestering microRNAs and so affecting their regulation of gene expression.
- Laura Poliseno
- , Leonardo Salmena
- & Pier Paolo Pandolfi
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News & Views |
How to accurately bypass damage
Ultraviolet radiation can cause cancer through DNA damage — specifically, by linking adjacent thymine bases. Crystal structures show how the enzyme DNA polymerase η accurately bypasses such lesions, offering protection.
- Suse Broyde
- & Dinshaw J. Patel
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News & Views |
Decoy for microRNAs
Pseudogenes are considered to be defunct relatives of known genes. But there is some surprising news: pseudogenes are functional and could have a role in the control of cancer
1 . Two experts discuss the significance of these findings for understanding the regulation of gene expression and cancer biology.- Isidore Rigoutsos
- & Frank Furnari
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News |
The genome's shield from sunlight
Enzyme structure reveals how cells avoid DNA damage caused by ultraviolet rays.
- Heidi Ledford
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Letter |
Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning
During vertebrate development, the dorsal–ventral and anterior–posterior (A–P) body axes are determined first, after which left–right (L–R) asymmetry is established. But the molecular mechanism by which L–R symmetry is broken in reference to the other two axes is poorly understood. Here it is shown that two mouse genes, Vang1 and Vang2, which belong to the planar cell polarity family, are required to interpret the A–P patterning information and link it to L–R asymmetry.
- Hai Song
- , Jianxin Hu
- & Yingzi Yang
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Letter |
TFIIA and the transactivator Rap1 cooperate to commit TFIID for transcription initiation
Here, the early steps of activator-dependent transcription in yeast are examined by using cryo-electron microscopy to study the transcription activator Rap1 in complex with the general transcription factors TFIID and TFIIA and with yeast enhancer–promoter DNA. A model is proposed whereby interactions between Rap1 and TFIIA convey activating signals to TFIID. Moreover, a Rap1-dependent DNA loop is visualized between the enhancer and the promoter.
- Gabor Papai
- , Manish K. Tripathi
- & Patrick Schultz
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Letter |
TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus
Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE), but many treatment regimens cannot maintain disease control in SLE patients. Here it is shown that the stimulation of plasmacytoid dendritic cells through toll-like receptors TLR7 and TLR9 can account for the reduced activity of glucocorticoids to inhibit the type I interferon pathway in SLE patients. Thus inhibitors of TLR7 and TLR9 signalling might prove to be effective corticosteroid-sparing drugs.
- Cristiana Guiducci
- , Mei Gong
- & Franck J. Barrat
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Letter |
Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription
Small regulatory RNAs function both in the cytoplasm, inhibiting expression from messenger RNAs, and in the nucleus, silencing heterochromatin and preventing genome rearrangement. Now a new protein involved in RNA interference in the nucleus has been characterized. This protein, NRDE-2, associates with NRDE-3 and short interfering RNAs on nascent transcripts. This association prevents elongation of the transcripts by RNA polymerase II, making this a co-transcriptional form of gene silencing.
- Shouhong Guang
- , Aaron F. Bochner
- & Scott Kennedy
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Letter |
Tumour angiogenesis is reduced in the Tc1 mouse model of Down’s syndrome
Down's syndrome is caused by trisomy of chromosome 21, and it is known that the growth of certain tumours is reduced in this genetic disorder. Using a mouse model of Down's syndrome, several individual genes on chromosome 21 are now being proposed to mediate the effect on tumour growth and angiogenesis.
- Louise E. Reynolds
- , Alan R. Watson
- & Kairbaan M. Hodivala-Dilke
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Article |
Crystal structure of HIV-1 Tat complexed with human P-TEFb
Here the 2.1 Å crystal structure of human immunodeficiency virus (HIV) Tat protein complexed with the positive transcription elongation factor P-TEFb is reported. This shows that Tat binding changes the structure of P-TEFb, which may suggest opportunities for developing inhibitors that block only the form of P-TEFb used by the virus.
- Tahir H. Tahirov
- , Nigar D. Babayeva
- & David H. Price
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Letter |
Termination of autophagy and reformation of lysosomes regulated by mTOR
When cells are starved, the enzyme TOR is inhibited, inducing autophagy. In this process, autophagosomes sequester intracellular components and then fuse with lysosomes, producing autolysosomes in which cargo is degraded to regenerate nutrients. Now, a mechanism is revealed by which lysosomes are re-formed. When starvation conditions are prolonged, mTOR is re-activated; this attenuates autophagy and results in tubules and vesicles extruding from the autolysosome and maturing into functional lysosomes.
- Li Yu
- , Christina K. McPhee
- & Michael J. Lenardo
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Letter |
A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases
Topoisomerases are enzymes that transiently make breaks in DNA, to prevent the build-up of topological stress and tangles as the genome is transcribed, replicated or repaired. Type II topoisomerases have been postulated to use a two-metal mechanism to break duplex DNA. Now, the structure of the DNA-binding and cleavage core of a yeast type II topoisomerase has been solved, showing that the enzyme uses a variation of the classical mechanism, and can also carry out the type of cleavage performed by type IA topoisomerases.
- Bryan H. Schmidt
- , Alex B. Burgin
- & James M. Berger
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Article |
HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase
When oxygen levels drop in a tissue, the transcription factor hypoxia-inducible factor (HIF) is activated to regulate the cellular response. HIFα levels are increased in most solid tumours and this correlates with a poor prognosis, for unknown reasons. Here it is shown that HIF-1, the worm version of HIFα, protects germ cells from DNA-damage-induced death. It does this remotely, by increasing the production of the TYR-2 protein in distant neurons. Inhibiting a human TYR-2 homologue promotes apoptosis in melanoma cells.
- Ataman Sendoel
- , Ines Kohler
- & Michael O. Hengartner
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Research Highlights |
Genomics: Transposition trends
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Letter |
Relationship between nucleosome positioning and DNA methylation
Nucleosomes are composed of around 147 bases of DNA wrapped around an octamer of histone proteins. Here, a genome-wide analysis of nucleosome positioning in Arabidopsis thaliana has been combined with profiles of DNA methylation at single base resolution, revealing 10-base periodicities in the DNA methylation status of nucleosome-bound DNA. The results indicate that nucleosome positioning influences the pattern of DNA methylation throughout the genome.
- Ramakrishna K. Chodavarapu
- , Suhua Feng
- & Matteo Pellegrini
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Letter |
Principles of stop-codon reading on the ribosome
Stop codons in messenger RNA define when a protein sequence has been completely synthesized; such codons bind release factors (RFs), which cause the newly made protein to be released. Structures of RFs alone and in combination with the ribosome have been reported, but the energetics of the reaction in the presence of codons had not been determined. Here, molecular dynamics simulations of 14 termination complexes are used to define how termination is achieved and how the RFs distinguish different sequences.
- Johan Sund
- , Martin Andér
- & Johan Åqvist
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Letter |
Phenotypic robustness conferred by apparently redundant transcriptional enhancers
Transcriptional enhancers are segments of regulatory DNA located some distance from the coding region of a gene, and several of them may sometimes serve apparently redundant functions. These authors demonstrate in Drosophila that such 'redundant' enhancers, by contributing higher overall levels of transcription, ensure robustness of phenotypes against both genetic and environmental perturbations, for example mutations in other genes or temperature changes that would otherwise lead to aberrant development.
- Nicolás Frankel
- , Gregory K. Davis
- & David L. Stern
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Letter |
CD95 promotes tumour growth
CD95 is a classical death receptor protein that regulates tissue homeostasis by inducing cell death. Here it is shown, however, that cancer cells depend on CD95 for optimal growth. Without CD95, the incidence of ovarian cancer and liver cancer in mice is reduced, as is the size of any tumours. So CD95 is a double-edged sword, and it may be necessary to reduce, rather than enhance, its activity in order to kill tumour cells.
- Lina Chen
- , Sun-Mi Park
- & Marcus E. Peter
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Research Highlights |
Genomics: Not-so-dark genome
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Letter |
Structural basis for 5′-nucleotide base-specific recognition of guide RNA by human AGO2
The association of microRNAs with Argonaute proteins (AGOs) yields complexes regulating gene expression. Although bacterial and archaeal miRNAs show no sequence preference at their 5′ ends, eukaryotic miRNAs tend to have a 5′ U or A. Here the structure of the human AGO2 MID domain complexed with ribonucleotide monophosphates is solved, revealing specific interaction of UMP and AMP with a loop that discriminates against CMP or GMP, and explaining the observed preference.
- Filipp Frank
- , Nahum Sonenberg
- & Bhushan Nagar
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Letter |
Structure of the bifunctional isocitrate dehydrogenase kinase/phosphatase
The Escherichia coli isocitrate dehydrogenase kinase/phosphatase (AceK) is a bifunctional enzyme that can phosphorylate or dephosphorylate isocitrate dehydrogenase (ICDH) to either inactivate or activate it in response to environmental changes. Now the structures of AceK and the AceK–ICDH complex have been solved, revealing the conformational changes that occur when AceK changes from a kinase to a phosphatase and vice versa.
- Jimin Zheng
- & Zongchao Jia
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