目次

Editorials

マラリアワクチンに対し過大な期待が生じないよう、留意すべきだ。

High hopes p.271

Care must be taken not to raise unrealistic expectations for RTS,S malaria vaccine.

doi: 10.1038/502271b

研究の重要性を評価する際には、特定基準を重視することの影響や科学者の懸念に配慮し、評価手法を公開する必要がある。

The maze of impact metrics p.271

In deciding how to judge the impact of research, evaluators must take into account the effects of emphasizing particular measures — and be open about their methods.

doi: 10.1038/502271a

地球外知的生命体探査のこれまでの歩みを、もう一度振り返ってみよう。

Searching for life p.272

A look into the past frames our attempts to find extraterrestrial intelligence.

doi: 10.1038/502272a

News

米政府一部閉鎖で、NIHの研究にもじわじわと影響が。

NIH campus endures slow decay p.279

Experiments suffer from lack of lab materials and staff during US government shutdown.

doi: 10.1038/502279a

ノーベル化学賞は、巨大分子をコンピューターでモデル化した理論化学者に。

Modellers react to chemistry award p.280

Prize proves that theorists can measure up to experimenters.

doi: 10.1038/502280a

気候変動に関する政府間パネル(IPCC)の内部力学が活動成果にどう影響するかを、社会科学者が研究対象に。

Study aims to put IPCC under a lens p.281

Social scientists want to examine how climate panel’s internal dynamics affect outcomes.

doi: 10.1038/502281a

建設の遅れのため、ITERが研究計画を見直しへ。

ITER keeps eye on prize p.282

Construction delays force rethink of research programme, but fusion target still on track.

doi: 10.1038/502282a

英政府は、研究への活用を目指して患者の医療データの公開を推進しているが、障害も。

UK push to open up patients’ data p.283

Government faces obstacles to mining medical records.

doi: 10.1038/502283a

FDAがミトコンドリア置換治療の臨床試験を検討しているが、安全性や倫理問題を懸念する声も。

Regulators weigh benefits of ‘three-parent’ fertilization p.284

But critics say mitochondrial replacement carries safety and ethical concerns.

doi: 10.1038/502284a

Features

インパクト

Research evaluation: Impact p.287

Evaluating research output and judging which work to fund is getting harder.

doi: 10.1038/502287a

最後の審判の日

Research assessments: Judgement day p.288

Many governments are assessing the quality of university research, much to the dismay of some researchers.

doi: 10.1038/502288a

ゴールデン・クラブ

Science publishing: The golden club p.291

Publishing in the most prestigious journals can open doors, but their cachet is under attack.

doi: 10.1038/502291a

News & Views

フォーラム:ゲノミクス:がんを全体にわたって比較する

Genomics: Comparisons across cancers p.306

がんゲノムの解析は、1つの特定の疾患という枠を越えたところに移りつつあり、今や複数種の腫瘍の遺伝学的、エピジェネティクス的な特徴の比較が行われている。二人の研究者が、このような研究からはがんのどのような生物学的性質が分かるのか、またそれによって臨床治療の実践がどのような方向に向かうと予想されるのかを論じている。

doi: 10.1038/502306a

物理化学:分子のための櫛

Physical chemistry: Combs for molecules p.307

周波数コムと呼ばれるレーザーは、試料から分子スペクトルを数マイクロ秒の内に高い空間分解能で発生させるのに使われてきた。こうした性能が、リアルタイムでの顕微鏡観察の新たな展望につながっていく。

doi: 10.1038/502307a

幹細胞:in situ での再プログラム化

Stem cells: Reprogramming in situ p.309

細胞の幹細胞状態への再プログラム化が、遺伝的操作を施したマウスの組織で達成された。この結果は、将来の再生医学では、生体内で組織の運命を操作できるようになる可能性を示唆している。

doi: 10.1038/nature12559

宇宙物理学:超明るい超新星が増加中

Astrophysics: Super-luminous supernovae on the rise p.310

新たに行われた観測から、極度に明るい超新星の一部は、質量が非常に大きい星の核爆発ではないと考えられるようになった。これらは、通常の質量の星で起こる事象であって、中心部から供給される強力な磁気エネルギーによって輝いているらしい。

doi: 10.1038/502310a

がん:内部から殺す

Cancer: Killing from the inside p.312

リソソームは、細胞内の主要な分解区画だが、細胞死経路にも関わっている。既存の薬剤を使った研究で、リソソームはがん細胞を選択的に破壊するための優れた薬理学的標的となることが分かった。

doi: 10.1038/nature12692

材料科学:結合すべきか、すべきではないか

Materials science: To bind or not to bind p.313

粒子の細胞への結合を制御する方法を探すことは、生物医学研究における新分野につながる可能性がある。そういうわけで、粒子と細胞との相互作用の方向性を誘導する方法が見つかったことは、大きな関心を集めている。

doi: 10.1038/502313a

多発性硬化症:昔からある薬の新しい使い方

Multiple sclerosis: An old drug plays a new trick p.314

多発性硬化症では神経軸索を囲むミエリン鞘に損傷が生じるが、以前からパーキンソン病の治療薬として使われている薬剤がこのような損傷の修復を誘導することが分かった。この知見は、多発性硬化症に対する治療薬開発の新しい方向性を示している。

doi: 10.1038/nature12694

Perspective

医学:臨床試験でオミクスに基づく予測因子を使用するための基準

Criteria for the use of omics-based predictors in clinical trials OPEN p.317

The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to ‘omics’-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.

doi: 10.1038/nature12564

Articles

地球:地球上部マントルの拡散クリープ下で結晶方位がそろうカンラン石

Olivine crystals align during diffusion creep of Earth’s upper mantle p.321

In Earth’s mantle, the shape change of olivine grains depending on temperature and the presence of melt can result in the development of olivine crystallographic preferred orientation during diffusion creep, meaning that the process may be the principal mechanism of mantle flow.

doi: 10.1038/nature12570

創薬:多発性硬化症の治療における再生医学的手法

A regenerative approach to the treatment of multiple sclerosis p.327

Multiple sclerosis is associated with a deficiency in generation of mature oligodendroctyes; an image-based screen for oligodendrocyte differentiation inducers identified the compound benztropine, which enhances remyelination acting through muscarinic receptors and decreases clinical severity in a multiple sclerosis model system.

doi: 10.1038/nature12647

がん:主要な12種類のがんにおける突然変異の全体像とその意味

Mutational landscape and significance across 12 major cancer types OPEN p.333

As part of The Cancer Genome Atlas Pan-Cancer effort, data analysis for point mutations and small indels from 3,281 tumours and 12 tumour types is presented; among the findings are 127 significantly mutated genes from cellular processes with both established and emerging links in cancer, and an indication that the number of driver mutations required for oncogenesis is relatively small.

doi: 10.1038/nature12634

細胞:in vivoでの再プログラム化は分化全能性の特徴を持つiPS細胞および奇形腫を作り出す

Reprogramming in vivo produces teratomas and iPS cells with totipotency features p.340

Induced pluripotent stem cells (iPS cells) have been created in vivo by reprogramming mouse somatic cells with Oct4, Sox2, Klf4 and c-Myc; these cells have totipotent features that are missing from in vitro created iPS cells or embryonic stem cells.

doi: 10.1038/nature12586

Letters

宇宙:対不安定型超新星爆発ではない、ゆっくりと暗くなる超高輝度超新星

Slowly fading super-luminous supernovae that are not pair-instability explosions p.346

Super-luminous supernovae that radiate more than 1044 ergs per second at their peak luminosity have recently been discovered in faint galaxies at redshifts of 0.1–4. Some evolve slowly, resembling models of ‘pair-instability’ supernovae. Such models involve stars with original masses 140–260 times that of the Sun that now have carbon–oxygen cores of 65–130 solar masses. In these stars, the photons that prevent gravitational collapse are converted to electron–positron pairs, causing rapid contraction and thermonuclear explosions. Many solar masses of 56Ni are synthesized; this isotope decays to 56Fe via 56Co, powering bright light curves. Such massive progenitors are expected to have formed from metal-poor gas in the early Universe. Recently, supernova 2007bi in a galaxy at redshift 0.127 (about 12 billion years after the Big Bang) with a metallicity one-third that of the Sun was observed to look like a fading pair-instability supernova. Here we report observations of two slow-to-fade super-luminous supernovae that show relatively fast rise times and blue colours, which are incompatible with pair-instability models. Their late-time light-curve and spectral similarities to supernova 2007bi call the nature of that event into question. Our early spectra closely resemble typical fast-declining super-luminous supernovae, which are not powered by radioactivity. Modelling our observations with 10–16 solar masses of magnetar-energized ejecta demonstrates the possibility of a common explosion mechanism. The lack of unambiguous nearby pair-instability events suggests that their local rate of occurrence is less than 6 × 10−6 times that of the core-collapse rate.

doi: 10.1038/nature12569

量子物理学:パリティ測定とフィードバックによる超伝導キュービットの決定論的量子もつれ

Deterministic entanglement of superconducting qubits by parity measurement and feedback p.350

The stochastic evolution of quantum systems during measurement is arguably the most enigmatic feature of quantum mechanics. Measuring a quantum system typically steers it towards a classical state, destroying the coherence of an initial quantum superposition and the entanglement with other quantum systems. Remarkably, the measurement of a shared property between non-interacting quantum systems can generate entanglement, starting from an uncorrelated state. Of special interest in quantum computing is the parity measurement, which projects the state of multiple qubits (quantum bits) to a state with an even or odd number of excited qubits. A parity meter must discern the two qubit-excitation parities with high fidelity while preserving coherence between same-parity states. Despite numerous proposals for atomic, semiconducting and superconducting qubits, realizing a parity meter that creates entanglement for both even and odd measurement results has remained an outstanding challenge. Here we perform a time-resolved, continuous parity measurement of two superconducting qubits using the cavity in a three-dimensional circuit quantum electrodynamics architecture and phase-sensitive parametric amplification. Using postselection, we produce entanglement by parity measurement reaching 88 per cent fidelity to the closest Bell state. Incorporating the parity meter in a feedback-control loop, we transform the entanglement generation from probabilistic to fully deterministic, achieving 66 per cent fidelity to a target Bell state on demand. These realizations of a parity meter and a feedback-enabled deterministic measurement protocol provide key ingredients for active quantum error correction in the solid state.

doi: 10.1038/nature12513

光学:レーザー周波数コムを用いたコヒーレント・ラマンスペクトル画像化

Coherent Raman spectro-imaging with laser frequency combs p.355

Advances in optical spectroscopy and microscopy have had a profound impact throughout the physical, chemical and biological sciences. One example is coherent Raman spectroscopy, a versatile technique interrogating vibrational transitions in molecules. It offers high spatial resolution and three-dimensional sectioning capabilities that make it a label-free tool for the non-destructive and chemically selective probing of complex systems. Indeed, single-colour Raman bands have been imaged in biological tissue at video rates by using ultra-short-pulse lasers. However, identifying multiple, and possibly unknown, molecules requires broad spectral bandwidth and high resolution. Moderate spectral spans combined with high-speed acquisition are now within reach using multichannel detection or frequency-swept laser beams. Laser frequency combs are finding increasing use for broadband molecular linear absorption spectroscopy. Here we show, by exploring their potential for nonlinear spectroscopy, that they can be harnessed for coherent anti-Stokes Raman spectroscopy and spectro-imaging. The method uses two combs and can simultaneously measure, on the microsecond timescale, all spectral elements over a wide bandwidth and with high resolution on a single photodetector. Although the overall measurement time in our proof-of-principle experiments is limited by the waiting times between successive spectral acquisitions, this limitation can be overcome with further system development. We therefore expect that our approach of using laser frequency combs will not only enable new applications for nonlinear microscopy but also benefit other nonlinear spectroscopic techniques.

doi: 10.1038/nature12607

気候:大気中での硫酸–アミン粒子核形成の分子論的理解

Molecular understanding of sulphuric acid–amine particle nucleation in the atmosphere OPEN p.359

Nucleation of aerosol particles from trace atmospheric vapours is thought to provide up to half of global cloud condensation nuclei. Aerosols can cause a net cooling of climate by scattering sunlight and by leading to smaller but more numerous cloud droplets, which makes clouds brighter and extends their lifetimes. Atmospheric aerosols derived from human activities are thought to have compensated for a large fraction of the warming caused by greenhouse gases. However, despite its importance for climate, atmospheric nucleation is poorly understood. Recently, it has been shown that sulphuric acid and ammonia cannot explain particle formation rates observed in the lower atmosphere. It is thought that amines may enhance nucleation, but until now there has been no direct evidence for amine ternary nucleation under atmospheric conditions. Here we use the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN and find that dimethylamine above three parts per trillion by volume can enhance particle formation rates more than 1,000-fold compared with ammonia, sufficient to account for the particle formation rates observed in the atmosphere. Molecular analysis of the clusters reveals that the faster nucleation is explained by a base-stabilization mechanism involving acid–amine pairs, which strongly decrease evaporation. The ion-induced contribution is generally small, reflecting the high stability of sulphuric acid–dimethylamine clusters and indicating that galactic cosmic rays exert only a small influence on their formation, except at low overall formation rates. Our experimental measurements are well reproduced by a dynamical model based on quantum chemical calculations of binding energies of molecular clusters, without any fitted parameters. These results show that, in regions of the atmosphere near amine sources, both amines and sulphur dioxide should be considered when assessing the impact of anthropogenic activities on particle formation.

doi: 10.1038/nature12663

古生物学:カンブリア紀の大付属肢節足動物に見られる鋏角類神経の基本パターン

Chelicerate neural ground pattern in a Cambrian great appendage arthropod p.364

Preservation of neural tissue in early Cambrian arthropods has recently been demonstrated, to a degree that segmental structures of the head can be associated with individual brain neuromeres. This association provides novel data for addressing long-standing controversies about the segmental identities of specialized head appendages in fossil taxa. Here we document neuroanatomy in the head and trunk of a ‘great appendage’ arthropod, Alalcomenaeus sp., from the Chengjiang biota, southwest China, providing the most complete neuroanatomical profile known from a Cambrian animal. Micro-computed tomography reveals a configuration of one optic neuropil separate from a protocerebrum contiguous with four head ganglia, succeeded by eight contiguous ganglia in an eleven-segment trunk. Arrangements of optic neuropils, the brain and ganglia correspond most closely to the nervous system of Chelicerata of all extant arthropods, supporting the assignment of ‘great appendage’ arthropods to the chelicerate total group. The position of the deutocerebral neuromere aligns with the insertion of the great appendage, indicating its deutocerebral innervation and corroborating a homology between the ‘great appendage’ and chelicera indicated by morphological similarities. Alalcomenaeus and Fuxianhuia protensa demonstrate that the two main configurations of the brain observed in modern arthropods, those of Chelicerata and Mandibulata, respectively, had evolved by the early Cambrian.

doi: 10.1038/nature12520

神経科学:幼少マウスフェロモンは鋤鼻系を介して性行動を阻害する

A juvenile mouse pheromone inhibits sexual behaviour through the vomeronasal system p.368

Animals display a repertoire of different social behaviours. Appropriate behavioural responses depend on sensory input received during social interactions. In mice, social behaviour is driven by pheromones, chemical signals that encode information related to age, sex and physiological state. However, although mice show different social behaviours towards adults, juveniles and neonates, sensory cues that enable specific recognition of juvenile mice are unknown. Here we describe a juvenile pheromone produced by young mice before puberty, termed exocrine-gland secreting peptide 22 (ESP22). ESP22 is secreted from the lacrimal gland and released into tears of 2- to 3-week-old mice. Upon detection, ESP22 activates high-affinity sensory neurons in the vomeronasal organ, and downstream limbic neurons in the medial amygdala. Recombinant ESP22, painted on mice, exerts a powerful inhibitory effect on adult male mating behaviour, which is abolished in knockout mice lacking TRPC2, a key signalling component of the vomeronasal organ. Furthermore, knockout of TRPC2 or loss of ESP22 production results in increased sexual behaviour of adult males towards juveniles, and sexual responses towards ESP22-deficient juveniles are suppressed by ESP22 painting. Thus, we describe a pheromone of sexually immature mice that controls an innate social behaviour, a response pathway through the accessory olfactory system and a new role for vomeronasal organ signalling in inhibiting sexual behaviour towards young. These findings provide a molecular framework for understanding how a sensory system can regulate behaviour.

doi: 10.1038/nature12579

細胞生物学:糖尿病性高血糖はO結合型グリコシル化によりCaMKIIと不整脈を活性化する

Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation p.372

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca2+ handling and gene transcription. Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart and neurodegenerative diseases. Acute hyperglycaemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII autonomously, creating molecular memory even after Ca2+ concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum Ca2+ release events that can contribute to cardiac mechanical dysfunction and arrhythmias. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.

doi: 10.1038/nature12537

遺伝学:スタチンに依存したGATM発現のQTLが、スタチン誘発性ミオパチーに関連する

A statin-dependent QTL for GATM expression is associated with statin-induced myopathy p.377

Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.

doi: 10.1038/nature12508

分子生物学:HELQはRAD51パラログ依存的修復を促進して生殖細胞の消失と腫瘍形成を回避する

HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis p.381

Repair of interstrand crosslinks (ICLs) requires the coordinated action of the intra-S-phase checkpoint and the Fanconi anaemia pathway, which promote ICL incision, translesion synthesis and homologous recombination (reviewed in refs 1, 2). Previous studies have implicated the 3′–5′ superfamily 2 helicase HELQ in ICL repair in Drosophila melanogaster (MUS301 (ref. 3)) and Caenorhabditis elegans (HELQ-1 (ref. 4)). Although in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3′ single-stranded DNA overhangs and also disrupts protein–DNA interactions while translocating along DNA, little is known regarding its functions in mammalian organisms. Here we report that HELQ helicase-deficient mice exhibit subfertility, germ cell attrition, ICL sensitivity and tumour predisposition, with Helq heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. We establish that HELQ interacts directly with the RAD51 paralogue complex BCDX2 and functions in parallel to the Fanconi anaemia pathway to promote efficient homologous recombination at damaged replication forks. Thus, our results reveal a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour suppression in mammals.

doi: 10.1038/nature12565

生化学:見かけ上は非特異的なRNA結合タンパク質が持つ隠れた特異性

Hidden specificity in an apparently nonspecific RNA-binding protein p.385

Nucleic-acid-binding proteins are generally viewed as either specific or nonspecific, depending on characteristics of their binding sites in DNA or RNA. Most studies have focused on specific proteins, which identify cognate sites by binding with highest affinities to regions with defined signatures in sequence, structure or both. Proteins that bind to sites devoid of defined sequence or structure signatures are considered nonspecific. Substrate binding by these proteins is poorly understood, and it is not known to what extent seemingly nonspecific proteins discriminate between different binding sites, aside from those sequestered by nucleic acid structures. Here we systematically examine substrate binding by the apparently nonspecific RNA-binding protein C5, and find clear discrimination between different binding site variants. C5 is the protein subunit of the transfer RNA processing ribonucleoprotein enzyme RNase P from Escherichia coli. The protein binds 5′ leaders of precursor tRNAs at a site without sequence or structure signatures. We measure functional binding of C5 to all possible sequence variants in its substrate binding site, using a high-throughput sequencing kinetics approach (HITS-KIN) that simultaneously follows processing of thousands of RNA species. C5 binds different substrate variants with affinities varying by orders of magnitude. The distribution of functional affinities of C5 for all substrate variants resembles affinity distributions of highly specific nucleic acid binding proteins. Unlike these specific proteins, C5 does not bind its physiological RNA targets with the highest affinity, but with affinities near the median of the distribution, a region that is not associated with a sequence signature. We delineate defined rules governing substrate recognition by C5, which reveal specificity that is hidden in cellular substrates for RNase P. Our findings suggest that apparently nonspecific and specific RNA-binding modes may not differ fundamentally, but represent distinct parts of common affinity distributions.

doi: 10.1038/nature12543

遺伝学:切断により誘発される複製では、移動性の異常なバブル構造が保存的DNA合成を推進する

Migrating bubble during break-induced replication drives conservative DNA synthesis p.389

The repair of chromosomal double strand breaks (DSBs) is crucial for the maintenance of genomic integrity. However, the repair of DSBs can also destabilize the genome by causing mutations and chromosomal rearrangements, the driving forces for carcinogenesis and hereditary diseases. Break-induced replication (BIR) is one of the DSB repair pathways that is highly prone to genetic instability. BIR proceeds by invasion of one broken end into a homologous DNA sequence followed by replication that can copy hundreds of kilobases of DNA from a donor molecule all the way through its telomere. The resulting repaired chromosome comes at a great cost to the cell, as BIR promotes mutagenesis, loss of heterozygosity, translocations, and copy number variations, all hallmarks of carcinogenesis. BIR uses most known replication proteins to copy large portions of DNA, similar to S-phase replication. It has therefore been suggested that BIR proceeds by semiconservative replication; however, the model of a bona fide, stable replication fork contradicts the known instabilities associated with BIR such as a 1,000-fold increase in mutation rate compared to normal replication. Here we demonstrate that in budding yeast the mechanism of replication during BIR is significantly different from S-phase replication, as it proceeds via an unusual bubble-like replication fork that results in conservative inheritance of the new genetic material. We provide evidence that this atypical mode of DNA replication, dependent on Pif1 helicase, is responsible for the marked increase in BIR-associated mutations. We propose that the BIR mode of synthesis presents a powerful mechanism that can initiate bursts of genetic instability in eukaryotes, including humans.

doi: 10.1038/nature12584

遺伝学:Pif1ヘリカーゼおよびPolδは複製バブルの移動を介して組換え共役DNA合成を促進する

Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration p.393

During DNA repair by homologous recombination (HR), DNA synthesis copies information from a template DNA molecule. Multiple DNA polymerases have been implicated in repair-specific DNA synthesis, but it has remained unclear whether a DNA helicase is involved in this reaction. A good candidate DNA helicase is Pif1, an evolutionarily conserved helicase in Saccharomyces cerevisiae important for break-induced replication (BIR) as well as HR-dependent telomere maintenance in the absence of telomerase found in 10–15% of all cancers. Pif1 has a role in DNA synthesis across hard-to-replicate sites and in lagging-strand synthesis with polymerase δ (Polδ). Here we provide evidence that Pif1 stimulates DNA synthesis during BIR and crossover recombination. The initial steps of BIR occur normally in Pif1-deficient cells, but Polδ recruitment and DNA synthesis are decreased, resulting in premature resolution of DNA intermediates into half-crossovers. Purified Pif1 protein strongly stimulates Polδ-mediated DNA synthesis from a D-loop made by the Rad51 recombinase. Notably, Pif1 liberates the newly synthesized strand to prevent the accumulation of topological constraint and to facilitate extensive DNA synthesis via the establishment of a migrating D-loop structure. Our results uncover a novel function of Pif1 and provide insights into the mechanism of HR.

doi: 10.1038/nature12585

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