Molecular biology articles within Nature

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  • Letter |

    Normally, expression of bacterial DNA damage repair genes is repressed by the binding of LexA protein to SOS ‘boxes’ in their operators. DNA damage activates the RecA protein, which promotes autocleavage of LexA such that its repression is relieved and repair proteins are expressed. These authors solve several structures of LexA dimer bound to SOS box DNA, and find that the orientation of the DNA-binding wings can account for the strict intersite spacing.

    • Adrianna P. P. Zhang
    • , Ying Z. Pigli
    •  & Phoebe A. Rice
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Article |

    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
  • News & Views |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Article |

    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
  • News & Views |

    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
  • Letter |

    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
  • Letter |

    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
  • Article |

    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
  • Letter |

    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
  • Letter |

    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
  • Article |

    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
  • Letter |

    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
  • Article |

    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
  • News & Views |

    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
  • News & Views |

    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 cancer1. Two experts discuss the significance of these findings for understanding the regulation of gene expression and cancer biology.

    • Isidore Rigoutsos
    •  & Frank Furnari
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Article |

    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
  • Letter |

    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
  • Letter |

    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
  • Article |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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
  • Letter |

    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