Molecular biology articles within Nature

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  • Article |

    To investigate the core engine of the eukaryotic mitotic cycle, a minimal control network has been generated in fission yeast that efficiently sustains cellular reproduction. Orderly progression through the major events of the cell cycle is driven by oscillation of an engineered minimal CDK module lacking much of the canonical regulation.

    • Damien Coudreuse
    •  & Paul Nurse

  • Letter |

    During periods of fasting the liver produces ketone bodies, which the peripheral tissues can use as a source of energy. Here it is shown that fasting inhibits multi-component mTOR complex 1 (mTORC1) in the liver. Inhibition of mTORC1 is required for activation of PPARα, a master regulator that switches on genes involved in ketogenesis. Livers from aged mice have increased mTORC1 signalling, reduced PPARα activity, and reduced ketone production. The observation that mTORC1 promotes an ageing phenotype in the liver fits well with the observation that inhibition of this pathway increases lifespan in several organisms.

    • Shomit Sengupta
    • , Timothy R. Peterson
    •  & David M. Sabatini

  • Letter |

    The histone variant mH2A is shown to be expressed at reduced levels in many melanomas. Loss of mH2A promotes tumour growth and metastasis via transcriptional upregulation of CDK8, a known oncogene. This study therefore reveals a new tumour suppression mechanism exerted by epigenetic modifications.

    • Avnish Kapoor
    • , Matthew S. Goldberg
    •  & Emily Bernstein

  • Letter |

    Although loss of XLF, a classical non-homologous DNA end-joining (NHEJ) repair factor, shows strong effects in non-lymphoid cells, in lymphoid cells its absence has only modest effects on V(D)J recombination. This study now shows that in lymphoid cells, two other repair factors — ATM kinase and histone protein H2AX — have functional redundancy with XLF. Thus, mice deficient in both ATM and XLF have compromised conventional NHEJ, although alternative end-joining is retained. The results hint that the redundant function in end-joining that XLF has with both ATM and H2AX may have to do with an ATM role in chromatin accessibility.

    • Shan Zha
    • , Chunguang Guo
    •  & Frederick W. Alt

  • Letter |

    Antigen receptor loci contain numerous gene segments that are recombined in response to antigen stimulation. The RAG endonuclease makes the double-strand breaks that initiate recombination. The ends of these breaks are hairpins that can only be cleaved by the Artemis nuclease. Here, it is shown that the specificity for Artemis is dictated by the histone protein H2AX, in cooperation with the repair protein MDC-1. In the absence of H2AX, another nuclease, CtIP, can open the ends but they are not joined efficiently; this leads to genomic instability.

    • Beth A. Helmink
    • , Anthony T. Tubbs
    •  & Barry P. Sleckman

  • Letter |

    Identifying the genomic regulatory sequences, such as enhancers, that control early embryonic development remains a difficult challenge. Here, profiling of histone modifications and chromatin regulators in human embryonic stem cells (hESCs) reveals unique signatures that are used to identify over 2,000 putative enhancers. These enhancers are either active in the h ESCs or associated with early developmental genes.

    • Alvaro Rada-Iglesias
    • , Ruchi Bajpai
    •  & Joanna Wysocka

  • Letter |

    Studies have indicated an undefined role in DNA replication for CENP-B, a DNA binding protein associated with heterochromatin, centromeres and retrotransposon long terminal repeats (LTRs). Here it is shown that Sap1, which binds LTRs, promotes genomic instability when CENP-B activity is absent. CENP-B facilitates replication fork progression through LTRs in a way that protects against rearrangements.

    • Mikel Zaratiegui
    • , Matthew W. Vaughn
    •  & Robert A. Martienssen

  • Letter |

    The TET family of enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Mutations in the gene encoding TET2 are frequently observed in myeloid malignancies. Here it is shown that these disease-associated mutations compromise TET2 catalytic activity; bone marrow samples from patients with TET2 mutations have low levels of 5hmC in genomic DNA, and TET2 is required for normal haematopoietic differentiation. Measurement of genomic 5hmC levels may prove valuable as a diagnostic tool in myeloid cancers.

    • Myunggon Ko
    • , Yun Huang
    •  & Anjana Rao

  • Technology Feature |

    Developing techniques are helping researchers to build the protein interaction networks that underlie all cell functions.

    • Laura Bonetta

  • Letter |

    During translation, tRNAs enter the ribosome and then move sequentially through three sites, known as A, P and E, as they transfer their attached amino acids onto the growing peptide chain. How the ribosome facilitates tRNA translocation between the sites remains largely unknown. Now a study uses multiparticle cryoelectron microscopy of a ribosome bound to the translation elongation factor, EF-G, to get information about tRNA movement. It identifies two new substates and sees that translocation is linked to unratcheting of the 30S ribosomal subunit.

    • Andreas H. Ratje
    • , Justus Loerke
    •  & Christian M. T. Spahn

  • Letter |

    The E1 and E2 glycoproteins of alphaviruses form heterodimers and assemble into spikes on the virus surface, which mediate receptor binding and endocytosis. When the virion encounters acidic pH in the endosome E1 and E2 dissociate and E1 triggers fusion with the endosomal membrane. Two papers now provide the first crystal structures for glycoprotein complexes incorporating E2 at acidic and neutral pH, respectively. Together they provide insight into how fusion activation is controlled in alphaviruses.

    • James E. Voss
    • , Marie-Christine Vaney
    •  & Félix A. Rey

  • Letter |

    Here it is shown that reactivation of endogenous telomerase activity in mice extends telomeres, reduces DNA damage signalling, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease and the reversal of damage observed here support the development of regenerative strategies designed to restore telomere integrity.

    • Mariela Jaskelioff
    • , Florian L. Muller
    •  & Ronald A. DePinho

  • Letter |

    Protein machineries that move along the DNA, such as DNA polymerases and helicases, will necessarily encounter other bound proteins interacting with specific sites. Using 'curtains' of labelled DNA, this study measured whether such bound proteins interfere with the activity of the bacterial DNA translocase RecBCD. The translocase is able to push the proteins over nonspecific sites for thousands of base pairs before they are displaced.

    • Ilya J. Finkelstein
    • , Mari-Liis Visnapuu
    •  & Eric C. Greene

  • Letter |

    p53 is an important tumour suppressor gene. Two papers now show in a Kras-driven lung cancer model that p53-mediated tumour suppression is only engaged late during tumour progression, when the Kras oncogenic signal reaches a threshold sufficient to activate the ARF–p53 pathway. Therefore, p53 re-expression in p53-deficient lung tumours does not restrict early stages of tumorigenesis, but induces tumour regression of more aggressive tumours.

    • Melissa R. Junttila
    • , Anthony N. Karnezis
    •  & Carla P. Martins

  • Letter |

    Lipid asymmetry can be disrupted during biological processes such as apoptosis, during which phosphatidylserine in the inner leaflet of the membrane is exposed on the outer membrane. It has been proposed that activation of a phospholipid scramblase catalyses bidirectional transbilayer movement of phospholipids, but the protein corresponding to this activity has not been identified. Here, the protein TMEM16F is identified, and is an essential component for the Ca2+-dependent exposure of phosphatidylserine on the plasma membrane. A patient with Scott syndrome, which results from a defect in phospholipid scrambling activity, was found to carry a mutation in the gene encoding TMEM16F.

    • Jun Suzuki
    • , Masato Umeda
    •  & Shigekazu Nagata

  • Article |

    tRNAs are synthesized in a premature form that requires trimming of the 5′ and 3′ ends and modification of specific nucleotides. RNase P, a complex containing a long catalytic RNA and a protein cofactor, catalyses the cleavage that generates the mature 5′ end. Here, the structure of RNase P bound to mature tRNAPhe is solved. Recognition of the leader sequence and its mechanism of cleavage is determined by soaking an oligonucleotide corresponding to the premature 5′ end into the crystal.

    • Nicholas J. Reiter
    • , Amy Osterman
    •  & Alfonso Mondragón

  • News & Views |

    Many bacteria and archaea protect themselves from viruses and other invasive genomes through a genetic interference pathway. The small RNAs that guide this defence specify the direct cleavage of foreign DNA. See Article p.67

    • Erik J. Sontheimer
    •  & Luciano A. Marraffini

  • News & Views |

    The protein angiotensinogen must undergo conformational changes to be cleaved into a precursor of the hormone angiotensin, which increases blood pressure. Oxidative stress seems to mediate this structural alteration. See Letter p.108

    • Curt D. Sigmund

  • Letter |

    Here, human genome-wide single-nucleotide polymorphism (SNP) data from more than 15,000 parent–offspring pairs have been used to construct the first recombination maps that are based on directly observed recombination events. The data reveal interesting differences between the sexes: for instance, in males recombination tends to shuffle exons, whereas in females it generates new combinations of nearby genes. Comparison of these maps with others also reveals population differences.

    • Augustine Kong
    • , Gudmar Thorleifsson
    •  & Kari Stefansson

  • Letter |

    Various biological processes are entrained by the day–night cycle to occur at a specific time of day. One way the circadian system exerts these effects is through post-transcriptional regulation. These authors show that a protein that transfers methyl groups onto several spliceosome subunits, PRMT5, is regulated by the light–dark cycle. Methylation of these subunits affects alternative splicing of some genes, thus making them subject to circadian control.

    • Sabrina E. Sanchez
    • , Ezequiel Petrillo
    •  & Marcelo J. Yanovsky

  • Letter |

    Piwi-associated RNAs (piRNAs) are small RNAs with several functions in the germline, such as repressing transposable elements and helping to maintain germline stem cells. Now, a function for piRNAs has been discovered outside the germline, in the fruitfly embryo. Specifically, piRNAs are required for the decay of the messenger RNA encoding the posterior morphogen Nanos. When piRNA-induced regulation is impaired, this mRNA is stabilized and developmental defects ensue.

    • Christel Rouget
    • , Catherine Papin
    •  & Martine Simonelig

  • Article |

    DEAD-box helicases use ATP hydrolysis to unwind duplex RNA and facilitate RNA or RNA–protein remodelling. One such helicase is Mss116, which targets a particular group II intron in RNA. Here, single-molecule fluorescence was used to monitor the effect of Mss16 on a minimal construct containing this intron. The data show that Mss16 stimulates the sampling of different folded states of the RNA. Moreover, the helicase promotes RNA folding through discrete ATP-independent and ATP-dependent steps.

    • Krishanthi S. Karunatilaka
    • , Amanda Solem
    •  & David Rueda

  • Letter |

    To facilitate their proper segregation, duplicated meiotic chromosomes are physically joined by crossovers. Crossover formation begins with the introduction of meiosis-specific double-strand breaks. These authors identify a new gene in Caenorhabditis elegans, xnd-1, that is required for crossover distribution on both the X and the autosomal chromosomes. Preliminary data suggest that xnd-1 does this by regulating acetylation of histone H2A on lysine 5.

    • Cynthia R. Wagner
    • , Lynnette Kuervers
    •  & Judith L. Yanowitz

  • News & Views |

    Purification of the human tumour-suppressor protein BRCA2, which is crucial for DNA repair, has been a formidable challenge owing to its large size. That mission is now accomplished, providing biochemical insight. See Article p.678

    • Lee Zou

  • Letter |

    Angiotensins have a crucial role in blood pressure regulation and are generated by cleavage of a larger protein, angiotensinogen, by the enzyme renin. Structures of angiotensinogen alone and in complex with renin show that a large conformational change is required to expose the renin-cleavage site. The authors also show that this transition is regulated by oxidation and that women with pre-eclampsia have higher levels of the more active, oxidized, form.

    • Aiwu Zhou
    • , Robin W. Carrell
    •  & Randy J. Read

  • Letter |

    Here it is shown that the end products of lipid oxidation — ω-(2-carboxyethyl) pyrrole and other related pyrroles — are generated during inflammation and wound healing, and accumulate at high levels in ageing tissues in mice and in highly vascularized tumours in murine and human melanomas. These carboxyalkylpyrroles are recognized by Toll-like receptor 2 on endothelial cells, setting off a chain of events that leads to the growth of new blood vessels.

    • Xiaoxia Z. West
    • , Nikolay L. Malinin
    •  & Tatiana V. Byzova

  • Article |

    DNA bases that are alkylated or deaminated are removed by DNA glycosylase repair enzymes. In structures of several other DNA glycosylases, the modified base inserts into the active site. These authors solve the structure of glycosylase AlkD, find that the modified base is extruded in an extrahelical position and propose a model for how this solvent-exposed position allows cleavage of N3- and N7-alkylated bases specifically.

    • Emily H. Rubinson
    • , A. S. Prakasha Gowda
    •  & Brandt F. Eichman

  • Letter |

    In most bacteria and all archaea, glutamyl-tRNA synthetase (GluRS) glutamylates both tRNAGlu and tRNAGln; Glu-tRNAGln is then converted to Gln-tRNAGln by an amidotransferase. Here the structure is reported of a bacterial complex containing tRNAGln, GluRS and the amidotransferase GatCAB. The structure provides an explanation for how the enzymes work consecutively: only one can assume a productive state at any time. There also seems to be an intermediary state in which neither enzyme is productive.

    • Takuhiro Ito
    •  & Shigeyuki Yokoyama

  • Article |

    Splicing is carried out by a collection of protein–RNA complexes known as snRNPs. The spliceosome contains equal quantities of the U1, U2, U4, U5 and U6 snRNPs, but the U1 snRNP is made in levels excess to the amounts needed to form spliceosomes, leading to the idea that excess U1s might have splicing independent functions. Here it is shown that the U1 snRNA interacts with some pre mRNAs whose introns have cryptic polyadenylation sites. This interaction prevents premature termination and polyadenylation of the pre mRNA.

    • Daisuke Kaida
    • , Michael G. Berg
    •  & Gideon Dreyfuss

  • Letter |

    Two classes of enzyme — cyclin-dependent kinases (CDK) and Dbf4-dependent kinase (DDK) — facilitate the initiation of DNA replication in eukaryotes. It is now shown that, when DNA damage is sensed, another kinase, Rad53, halts the firing of late replication origins by inhibiting both the CDK and the DDK pathways. Rad53 acts on DDK directly by inhibiting Dbf4, whereas the CDK pathway is blocked by Rad53-mediated phosphorylation of the downstream CDK substrate Sld3.

    • Jaime Lopez-Mosqueda
    • , Nancy L. Maas
    •  & David P. Toczyski

  • News & Views |

    Plasmodium falciparum is the agent of the deadliest form of human malaria. A survey of Plasmodium diversity in African apes reveals that western gorillas are the reservoir species for this parasite. See Article p. 420

    • Edward C. Holmes

  • News & Views |

    Enhancer sequences increase gene transcription with the help of a co-activator complex, the Mediator. Another protein complex — cohesin — seems to work with Mediator to bring together enhancers and promoters. See Article p. 430

    • Rolf Ohlsson

  • News & Views |

    Methods for generating embryonic-like stem cells have been established. The focus now is on finding ways to coax these cells into matching their natural counterparts as closely as possible, should this be desired.

    • Thomas P. Zwaka

  • Letter |

    Two classes of enzyme — cyclin-dependent kinases (CDK) and Dbf4-dependent kinase (DDK) — facilitate the initiation of DNA replication in eukaryotes. It is now shown that, when DNA damage is sensed, another kinase, Rad53, halts the firing of late replication origins by inhibiting both the CDK and the DDK pathways. Rad53 acts on DDK directly by inhibiting Dbf4, whereas the CDK pathway is blocked by Rad53-mediated phosphorylation of the downstream CDK substrate Sld3.

    • Philip Zegerman
    •  & John F. X. Diffley

  • Letter |

    The translation of messenger RNA that lacks stop codons results in the production of aberrant proteins, which may have harmful effects on the cell. It is unclear how eukaryotic cells eliminate these 'non-stop' proteins. Here it is shown that, in Saccharomyces cerevisiae, an E3 ubiquitin ligase called Ltn1 acts in the quality-control pathway. It associates with ribosomes and marks non-stop proteins with ubiquitin, which targets the proteins for degradation.

    • Mario H. Bengtson
    •  & Claudio A. P. Joazeiro

  • Letter |

    The ends of chromosomes, known as telomeres, look like ends generated by double-strand breaks, but if treated as such the DNA damage repair system would initiate a checkpoint response and cause telomere–telomere fusions. These authors show that telomeres lack two types of histone modification that are required for recruitment of Crb2b53BP1, without which the checkpoint cannot be activated even if other DNA damage response proteins are recruited to a Taz1-deficient telomere.

    • Tiago Carneiro
    • , Lyne Khair
    •  & Miguel Godinho Ferreira

  • Letter |

    Transport of solutes across biological membranes is carried out by specialized secondary transport proteins in the lipid bilayer. These authors report structures of the sodium-independent carnitine/butyrobetaine antiporter CaiT from two microorganisms. The three-dimensional architecture of CaiT resembles that of the Na+-dependent transporters LeuT and BetP, but in CaiT a methionine sulphur takes the place of the Na+ ion to coordinate the substrate in the central transport site, enabling Na+-independent transport to occur.

    • Sabrina Schulze
    • , Stefan Köster
    •  & Werner Kühlbrandt

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