네이처 컨텐츠

Editorials

Counting the cost p.461

As more and more of its ocean-sciences budget is eaten up by operational and maintenance costs, the US National Science Foundation should learn to take a long view when investing in major projects.

doi: 10.1038/501461a

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Time for change p.461

Angela Merkel needs to tackle the issue of Germany’s uneven university funding.

doi: 10.1038/501461b

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Homes for bones p.462

A dispute over the skull of an Italian cheese thief highlights the enduring debate over repatriation.

doi: 10.1038/501462a

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News

Features

The start-up engine p.476

Third Rock Ventures made its name by placing big bets on the biotechnology companies it launched. Now, everyone is waiting for the pay-off.

Heidi Ledford

doi: 10.1038/501476a

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Oceanography's billion-dollar baby p.480

A mammoth undersea US project will soon start streaming data to researchers. But some wonder whether the system is worth its high price.

Alexandra Witze

doi: 10.1038/501480a

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News & Views

Temperate hotspots p.494

The inclusion of abundance data in global surveys of reef fishes reveals new hotspots of functional biodiversity, not all of which show high species richness. The findings may influence conservation priorities. See Letter p.539

Derek P. Tittensor

doi: 10.1038/501494a

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The carbon-nanotube computer has arrived p.495

The most complex electronic device yet built from carbon nanotubes has been demonstrated. The system is a functional universal computer, and represents a significant advance in the field of emerging electronic materials. See Letter p.526

Franz Kreupl

doi: 10.1038/501495a

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A resolution of the Archaean paradox p.496

A model of early Earth, in which heat from the interior is carried to the surface through volcanic heat pipes, suggests that our planet 4 billion years ago had more in common with Jupiter's moon Io than with today's Earth. See Article p.501

Louis Moresi

doi: 10.1038/501496a

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Rotating molecules as quantum magnets p.497

The push to engineer and probe quantum many-body systems using ultracold gases has reached a milestone with the observation of controlled dynamics caused by interactions between distant molecules trapped in a lattice. See Letter p.521

Andrew J. Daley

doi: 10.1038/nature12560

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A table for two p.498

Autophagy, the process of cellular self-cannibalism, comes in various forms. It now emerges that two of these — mitophagy and xenophagy — share a common initiator protein, Parkin. See Article p.512

Marcel A. Behr & Erwin Schurr

doi: 10.1038/nature12555

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Articles

Heat-pipe Earth p.501

A heat-pipe model of Earth, whereby interior heat is brought to the surface through localized channels, yields predictions that agree with craton data and the detrital zircon record, and offers a global geodynamic framework in which to explore Earth’s evolution before the onset of plate tectonics.

William B. Moore & A. Alexander G. Webb

doi: 10.1038/nature12473

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Transcriptome and genome sequencing uncovers functional variation in humans p.506

Sequencing and deep analysis of mRNA and miRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project reveal widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent, and the analyses point to putative causal variants for dozens of disease-associated loci.

Tuuli Lappalainen, Michael Sammeth, Marc R. Friedländer, Peter A. C. ‘t Hoen, Jean Monlong, Manuel A. Rivas, Mar Gonzàlez-Porta, Natalja Kurbatova, Thasso Griebel, Pedro G. Ferreira + et al.

doi: 10.1038/nature12531

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The ubiquitin ligase parkin mediates resistance to intracellular pathogens p.512

Mutations in the ubiquitin ligase parkin are associated with increased susceptibility to Parkinson’s disease; parkin is already known to have a role in mitophagy and this work identifies a new innate immunity role for parkin in ubiquitin-mediated autophagy of intracellular bacterial pathogens.

Paolo S. Manzanillo, Janelle S. Ayres, Robert O. Watson, Angela C. Collins, Gianne Souza, Chris S. Rae, David S. Schneider, Ken Nakamura, Michael U. Shiloh & Jeffery S. Cox

doi: 10.1038/nature12566

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Letters

Swings between rotation and accretion power in a binary millisecond pulsar p.517

It is thought that neutron stars in low-mass binary systems can accrete matter and angular momentum from the companion star and be spun-up to millisecond rotational periods. During the accretion stage, the system is called a low-mass X-ray binary, and bright X-ray emission is observed. When the rate of mass transfer decreases in the later evolutionary stages, these binaries host a radio millisecond pulsar whose emission is powered by the neutron star’s rotating magnetic field. This evolutionary model is supported by the detection of millisecond X-ray pulsations from several accreting neutron stars and also by the evidence for a past accretion disc in a rotation-powered millisecond pulsar. It has been proposed that a rotation-powered pulsar may temporarily switch on during periods of low mass inflow in some such systems. Only indirect evidence for this transition has hitherto been observed. Here we report observations of accretion-powered, millisecond X-ray pulsations from a neutron star previously seen as a rotation-powered radio pulsar. Within a few days after a month-long X-ray outburst, radio pulses were again detected. This not only shows the evolutionary link between accretion and rotation-powered millisecond pulsars, but also that some systems can swing between the two states on very short timescales.

A. Papitto, C. Ferrigno, E. Bozzo, N. Rea, L. Pavan, L. Burderi, M. Burgay, S. Campana, T. Di Salvo, M. Falanga + et al.

doi: 10.1038/nature12470

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Observation of dipolar spin-exchange interactions with lattice-confined polar molecules p.521

With the production of polar molecules in the quantum regime, long-range dipolar interactions are expected to facilitate understanding of strongly interacting many-body quantum systems and to realize lattice spin models for exploring quantum magnetism. In ordinary atomic systems, where contact interactions require wavefunction overlap, effective spin interactions on a lattice can be mediated by tunnelling, through a process referred to as superexchange; however, the coupling is relatively weak and is limited to nearest-neighbour interactions. In contrast, dipolar interactions exist even in the absence of tunnelling and extend beyond nearest neighbours. This allows coherent spin dynamics to persist even for gases with relatively high entropy and low lattice filling. Measured effects of dipolar interactions in ultracold molecular gases have been limited to the modification of inelastic collisions and chemical reactions. Here we use dipolar interactions of polar molecules pinned in a three-dimensional optical lattice to realize a lattice spin model. Spin is encoded in rotational states of molecules that are prepared and probed by microwaves. Resonant exchange of rotational angular momentum between two molecules realizes a spin-exchange interaction. The dipolar interactions are apparent in the evolution of the spin coherence, which shows oscillations in addition to an overall decay of the coherence. The frequency of these oscillations, the strong dependence of the spin coherence time on the lattice filling factor and the effect of a multipulse sequence designed to reverse dynamics due to two-body exchange interactions all provide evidence of dipolar interactions. Furthermore, we demonstrate the suppression of loss in weak lattices due to a continuous quantum Zeno mechanism. Measurements of these tunnelling-induced losses allow us to determine the lattice filling factor independently. Our work constitutes an initial exploration of the behaviour of many-body spin models with direct, long-range spin interactions and lays the groundwork for future studies of many-body dynamics in spin lattices.

Bo Yan, Steven A. Moses, Bryce Gadway, Jacob P. Covey, Kaden R. A. Hazzard, Ana Maria Rey, Deborah S. Jin & Jun Ye

doi: 10.1038/nature12483

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Carbon nanotube computer p.526

The miniaturization of electronic devices has been the principal driving force behind the semiconductor industry, and has brought about major improvements in computational power and energy efficiency. Although advances with silicon-based electronics continue to be made, alternative technologies are being explored. Digital circuits based on transistors fabricated from carbon nanotubes (CNTs) have the potential to outperform silicon by improving the energy–delay product, a metric of energy efficiency, by more than an order of magnitude. Hence, CNTs are an exciting complement to existing semiconductor technologies. Owing to substantial fundamental imperfections inherent in CNTs, however, only very basic circuit blocks have been demonstrated. Here we show how these imperfections can be overcome, and demonstrate the first computer built entirely using CNT-based transistors. The CNT computer runs an operating system that is capable of multitasking: as a demonstration, we perform counting and integer-sorting simultaneously. In addition, we implement 20 different instructions from the commercial MIPS instruction set to demonstrate the generality of our CNT computer. This experimental demonstration is the most complex carbon-based electronic system yet realized. It is a considerable advance because CNTs are prominent among a variety of emerging technologies that are being considered for the next generation of highly energy-efficient electronic systems.

Max M. Shulaker, Gage Hills, Nishant Patil, Hai Wei, Hong-Yu Chen, H.-S. Philip Wong & Subhasish Mitra

doi: 10.1038/nature12502

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Alkane desaturation by concerted double hydrogen atom transfer to benzyne p.531

The removal of two vicinal hydrogen atoms from an alkane to produce an alkene is a challenge for synthetic chemists. In nature, desaturases and acetylenases are adept at achieving this essential oxidative functionalization reaction, for example during the biosynthesis of unsaturated fatty acids, eicosanoids, gibberellins and carotenoids. Alkane-to-alkene conversion almost always involves one or more chemical intermediates in a multistep reaction pathway; these may be either isolable species (such as alcohols or alkyl halides) or reactive intermediates (such as carbocations, alkyl radicals, or σ-alkyl-metal species). Here we report a desaturation reaction of simple, unactivated alkanes that is mechanistically unique. We show that benzynes are capable of the concerted removal of two vicinal hydrogen atoms from a hydrocarbon. The discovery of this exothermic, net redox process was enabled by the simple thermal generation of reactive benzyne intermediates through the hexadehydro-Diels–Alder cycloisomerization reaction of triyne substrates. We are not aware of any single-step, bimolecular reaction in which two hydrogen atoms are simultaneously transferred from a saturated alkane. Computational studies indicate a preferred geometry with eclipsed vicinal C–H bonds in the alkane donor.

Dawen Niu, Patrick H. Willoughby, Brian P. Woods, Beeraiah Baire & Thomas R. Hoye

doi: 10.1038/nature12492

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Atmospheric oxygenation three billion years ago p.535

It is widely assumed that atmospheric oxygen concentrations remained persistently low (less than 10−5 times present levels) for about the first 2 billion years of Earth’s history. The first long-term oxygenation of the atmosphere is thought to have taken place around 2.3 billion years ago, during the Great Oxidation Event. Geochemical indications of transient atmospheric oxygenation, however, date back to 2.6–2.7 billion years ago. Here we examine the distribution of chromium isotopes and redox-sensitive metals in the approximately 3-billion-year-old Nsuze palaeosol and in the near-contemporaneous Ijzermyn iron formation from the Pongola Supergroup, South Africa. We find extensive mobilization of redox-sensitive elements through oxidative weathering. Furthermore, using our data we compute a best minimum estimate for atmospheric oxygen concentrations at that time of 3 × 10−4 times present levels. Overall, our findings suggest that there were appreciable levels of atmospheric oxygen about 3 billion years ago, more than 600 million years before the Great Oxidation Event and some 300–400 million years earlier than previous indications for Earth surface oxygenation.

Sean A. Crowe, Lasse N. Døssing, Nicolas J. Beukes, Michael Bau, Stephanus J. Kruger, Robert Frei & Donald E. Canfield

doi: 10.1038/nature12426

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Integrating abundance and functional traits reveals new global hotspots of fish diversity p.539

Species richness has dominated our view of global biodiversity patterns for centuries. The dominance of this paradigm is reflected in the focus by ecologists and conservation managers on richness and associated occurrence-based measures for understanding drivers of broad-scale diversity patterns and as a biological basis for management. However, this is changing rapidly, as it is now recognized that not only the number of species but the species present, their phenotypes and the number of individuals of each species are critical in determining the nature and strength of the relationships between species diversity and a range of ecological functions (such as biomass production and nutrient cycling). Integrating these measures should provide a more relevant representation of global biodiversity patterns in terms of ecological functions than that provided by simple species counts. Here we provide comparisons of a traditional global biodiversity distribution measure based on richness with metrics that incorporate species abundances and functional traits. We use data from standardized quantitative surveys of 2,473 marine reef fish species at 1,844 sites, spanning 133 degrees of latitude from all ocean basins, to identify new diversity hotspots in some temperate regions and the tropical eastern Pacific Ocean. These relate to high diversity of functional traits amongst individuals in the community (calculated using Rao’s Q), and differ from previously reported patterns in functional diversity and richness for terrestrial animals, which emphasize species-rich tropical regions only. There is a global trend for greater evenness in the number of individuals of each species, across the reef fish species observed at sites (‘community evenness’), at higher latitudes. This contributes to the distribution of functional diversity hotspots and contrasts with well-known latitudinal gradients in richness. Our findings suggest that the contribution of species diversity to a range of ecosystem functions varies over large scales, and imply that in tropical regions, which have higher numbers of species, each species contributes proportionally less to community-level ecological processes on average than species in temperate regions. Metrics of ecological function usefully complement metrics of species diversity in conservation management, including when identifying planning priorities and when tracking changes to biodiversity values.

Rick D. Stuart-Smith, Amanda E. Bates, Jonathan S. Lefcheck, J. Emmett Duffy, Susan C. Baker, Russell J. Thomson, Jemina F. Stuart-Smith, Nicole A. Hill, Stuart J. Kininmonth, Laura Airoldi + et al.

doi: 10.1038/nature12529

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A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex p.543

Early sensory experience instructs the maturation of neural circuitry in the cortex. This has been studied extensively in the primary visual cortex, in which loss of vision to one eye permanently degrades cortical responsiveness to that eye, a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process, but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in the primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following twenty-four hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates after monocular deprivation results from a rapid, although transient, reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV-cell-evoked responses after monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmacogenetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of layer 2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ODP.

Sandra J. Kuhlman, Nicholas D. Olivas, Elaine Tring, Taruna Ikrar, Xiangmin Xu & Joshua T. Trachtenberg

doi: 10.1038/nature12485

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The BC component of ABC toxins is an RHS-repeat-containing protein encapsulation device p.547

The ABC toxin complexes produced by certain bacteria are of interest owing to their potent insecticidal activity and potential role in human disease. These complexes comprise at least three proteins (A, B and C), which must assemble to be fully toxic. The carboxy-terminal region of the C protein is the main cytotoxic component, and is poorly conserved between different toxin complexes. A general model of action has been proposed, in which the toxin complex binds to the cell surface via the A protein, is endocytosed, and subsequently forms a pH-triggered channel, allowing the translocation of C into the cytoplasm, where it can cause cytoskeletal disruption in both insect and mammalian cells. Toxin complexes have been visualized using single-particle electron microscopy, but no high-resolution structures of the components are available, and the role of the B protein in the mechanism of toxicity remains unknown. Here we report the three-dimensional structure of the complex formed between the B and C proteins, determined to 2.5 Å by X-ray crystallography. These proteins assemble to form an unprecedented, large hollow structure that encapsulates and sequesters the cytotoxic, C-terminal region of the C protein like the shell of an egg. The shell is decorated on one end by a β-propeller domain, which mediates attachment of the B–C heterodimer to the A protein in the native complex. The structure reveals how C auto-proteolyses when folded in complex with B. The C protein is the first example, to our knowledge, of a structure that contains rearrangement hotspot (RHS) repeats, and illustrates a marked structural architecture that is probably conserved across both this widely distributed bacterial protein family and the related eukaryotic tyrosine-aspartate (YD)-repeat-containing protein family, which includes the teneurins. The structure provides the first clues about the function of these protein repeat families, and suggests a generic mechanism for protein encapsulation and delivery.

Jason N. Busby, Santosh Panjikar, Michael J. Landsberg, Mark R. H. Hurst & J. Shaun Lott

doi: 10.1038/nature12465

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Characterization of H7N9 influenza A viruses isolated from humans p.551

Avian influenza A viruses rarely infect humans; however, when human infection and subsequent human-to-human transmission occurs, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern owing to the appreciable case fatality rate associated with these infections (more than 25%), potential instances of human-to-human transmission, and the lack of pre-existing immunity among humans to viruses of this subtype. Here we characterize two early human A(H7N9) isolates, A/Anhui/1/2013 (H7N9) and A/Shanghai/1/2013 (H7N9); hereafter referred to as Anhui/1 and Shanghai/1, respectively. In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011 (H7N9); Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/4/2009 (H1N1pdm09); CA04). Anhui/1, Shanghai/1 and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates, Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs after intranasal inoculation. Critically, Anhui/1 transmitted through respiratory droplets in one of three pairs of ferrets. Glycan arrays showed that Anhui/1, Shanghai/1 and A/Hangzhou/1/2013 (H7N9) (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was found to be less sensitive in mice to neuraminidase inhibitors than a pandemic H1N1 2009 virus, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets and nonhuman primates and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.

Tokiko Watanabe, Maki Kiso, Satoshi Fukuyama, Noriko Nakajima, Masaki Imai, Shinya Yamada, Shin Murakami, Seiya Yamayoshi, Kiyoko Iwatsuki-Horimoto, Yoshihiro Sakoda + et al.

doi: 10.1038/nature12392

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Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice p.556

On 29 March 2013, the Chinese Center for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A(H7N9) virus. The recent human infections with H7N9 virus, totalling over 130 cases with 39 fatalities to date, have been characterized by severe pulmonary disease and acute respiratory distress syndrome (ARDS). This is concerning because H7 viruses have typically been associated with ocular disease in humans, rather than severe respiratory disease. This recent outbreak underscores the need to better understand the pathogenesis and transmission of these viruses in mammals. Here we assess the ability of A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9) viruses, isolated from fatal human cases, to cause disease in mice and ferrets and to transmit to naive animals. Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses. The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like α2,6-linked sialosides. Our results indicate that H7N9 viruses have the capacity for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus.

Jessica A. Belser, Kortney M. Gustin, Melissa B. Pearce, Taronna R. Maines, Hui Zeng, Claudia Pappas, Xiangjie Sun, Paul J. Carney, Julie M. Villanueva, James Stevens + et al.

doi: 10.1038/nature12391

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Limited airborne transmission of H7N9 influenza A virus between ferrets p.560

Wild waterfowl form the main reservoir of influenza A viruses, from which transmission occurs directly or indirectly to various secondary hosts, including humans. Direct avian-to-human transmission has been observed for viruses of subtypes A(H5N1), A(H7N2), A(H7N3), A(H7N7), A(H9N2) and A(H10N7) upon human exposure to poultry, but a lack of sustained human-to-human transmission has prevented these viruses from causing new pandemics. Recently, avian A(H7N9) viruses were transmitted to humans, causing severe respiratory disease and deaths in China. Because transmission via respiratory droplets and aerosols (hereafter referred to as airborne transmission) is the main route for efficient transmission between humans, it is important to gain an insight into airborne transmission of the A(H7N9) virus. Here we show that although the A/Anhui/1/2013 A(H7N9) virus harbours determinants associated with human adaptation and transmissibility between mammals, its airborne transmissibility in ferrets is limited, and it is intermediate between that of typical human and avian influenza viruses. Multiple A(H7N9) virus genetic variants were transmitted. Upon ferret passage, variants with higher avian receptor binding, higher pH of fusion, and lower thermostability were selected, potentially resulting in reduced transmissibility. This A(H7N9) virus outbreak highlights the need for increased understanding of the determinants of efficient airborne transmission of avian influenza viruses between mammals.

Mathilde Richard, Eefje J. A. Schrauwen, Miranda de Graaf, Theo M. Bestebroer, Monique I. J. Spronken, Sander van Boheemen, Dennis de Meulder, Pascal Lexmond, Martin Linster, Sander Herfst + et al.

doi: 10.1038/nature12476

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Wapl is an essential regulator of chromatin structure and chromosome segregation p.564

Mammalian genomes contain several billion base pairs of DNA that are packaged in chromatin fibres. At selected gene loci, cohesin complexes have been proposed to arrange these fibres into higher-order structures, but how important this function is for determining overall chromosome architecture and how the process is regulated are not well understood. Using conditional mutagenesis in the mouse, here we show that depletion of the cohesin-associated protein Wapl stably locks cohesin on DNA, leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes. These findings reveal that the stability of cohesin–DNA interactions is an important determinant of chromatin structure, and indicate that cohesin has an architectural role in interphase chromosome territories. Furthermore, we show that regulation of cohesin–DNA interactions by Wapl is important for embryonic development, expression of genes such as c-myc (also known as Myc), and cell cycle progression. In mitosis, Wapl-mediated release of cohesin from DNA is essential for proper chromosome segregation and protects cohesin from cleavage by the protease separase, thus enabling mitotic exit in the presence of functional cohesin complexes.

Antonio Tedeschi, Gordana Wutz, Sébastien Huet, Markus Jaritz, Annelie Wuensche, Erika Schirghuber, Iain Finley Davidson, Wen Tang, David A. Cisneros, Venugopal Bhaskara + et al.

doi: 10.1038/nature12471

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Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes p.569

Replication fork maintenance pathways preserve chromosomes, but their faulty application at nonallelic repeats could generate rearrangements causing cancer, genomic disorders and speciation. Potential causal mechanisms are homologous recombination and error-free postreplication repair (EF-PRR). Homologous recombination repairs damage-induced DNA double-strand breaks (DSBs) and single-ended DSBs within replication. To facilitate homologous recombination, the recombinase RAD51 and mediator BRCA2 form a filament on the 3′ DNA strand at a break to enable annealing to the complementary sister chromatid while the RecQ helicase, BLM (Bloom syndrome mutated) suppresses crossing over to prevent recombination. Homologous recombination also stabilizes and restarts replication forks without a DSB. EF-PRR bypasses DNA incongruities that impede replication by ubiquitinating PCNA (proliferating cell nuclear antigen) using the RAD6–RAD18 and UBC13–MMS2–RAD5 ubiquitin ligase complexes. Some components are common to both homologous recombination and EF-PRR such as RAD51 and RAD18. Here we delineate two pathways that spontaneously fuse inverted repeats to generate unstable chromosomal rearrangements in wild-type mouse embryonic stem (ES) cells. Gamma-radiation induced a BLM-regulated pathway that selectively fused identical, but not mismatched, repeats. By contrast, ultraviolet light induced a RAD18-dependent pathway that efficiently fused mismatched repeats. Furthermore, TREX2 (a 3′→5′ exonuclease) suppressed identical repeat fusion but enhanced mismatched repeat fusion, clearly separating these pathways. TREX2 associated with UBC13 and enhanced PCNA ubiquitination in response to ultraviolet light, consistent with it being a novel member of EF-PRR. RAD18 and TREX2 also suppressed replication fork stalling in response to nucleotide depletion. Interestingly, replication fork stalling induced fusion for identical and mismatched repeats, implicating faulty replication as a causal mechanism for both pathways.

Lingchuan Hu, Tae Moon Kim, Mi Young Son, Sung-A Kim, Cory L. Holland, Satoshi Tateishi, Dong Hyun Kim, P. Renee Yew, Cristina Montagna, Lavinia C. Dumitrache + et al.

doi: 10.1038/nature12500

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A two-domain elevator mechanism for sodium/proton antiport p.573

Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli, for which both electron microscopy and crystal structures are available. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur. The only reported NhaA crystal structure so far is of the low pH inactivated form. Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.

Chiara Lee, Hae Joo Kang, Christoph von Ballmoos, Simon Newstead, Povilas Uzdavinys, David L. Dotson, So Iwata, Oliver Beckstein, Alexander D. Cameron & David Drew

doi: 10.1038/nature12484

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