Spatiotemporal regulation of posttranslational modifications in the DNA damage response
A timely and accurate cellular response to DNA damage requires tight regulation of the action of DNA damage response (DDR) proteins at lesions. A multitude of posttranslational modifications (PTMs) of chromatin and chromatin-associated proteins coordinates the recruitment of critical proteins that dictate the appropriate DNA repair pathway and enable the actual repair of lesions. Phosphorylation, ubiquitylation, SUMOylation, neddylation, poly(ADP-ribosyl)ation, acetylation, and methylation are among the DNA damage-induced PTMs that have taken center stage as important DDR regulators. Redundant and multivalent interactions ...
Source: EMBO Journal - January 3, 2016 Category: Molecular Biology Authors: Dantuma, N. P., van Attikum, H. Tags: DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics Review Source Type: research

PEPRs spice up plant immunity
Some pattern recognition receptors (PRRs) in plants, such as PEPRs, sense endogenous, damage-associated molecular patterns (DAMPs) that are released during pathogen infection. In this issue of The EMBO Journal, Yamada and colleagues show that genetic or pathogen-induced depletion of Arabidopsis BAK1, a co-receptor for multiple PRRs, primes immune activation through PEPRs. The work illustrates a link between pathogen-induced perturbation of BAK1 and DAMP signaling. (Source: EMBO Journal)
Source: EMBO Journal - January 3, 2016 Category: Molecular Biology Authors: Tang, D., Zhou, J.-M. Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction, Plant Biology News [amp ] Views Source Type: research

Putting chromatin in its place: the pioneer factor NeuroD1 modulates chromatin state to drive cell fate decisions
Cell fate decisions require the deployment of distinct transcriptional programmes—how this is controlled and orchestrated is a key question from basic developmental biology to regenerative medicine. In this issue of The EMBO Journal, Pataskar and Jung et al (Pataskar et al, 2015) demonstrate how the transcription factor NeuroD1 acts genome-wide to elicit a specific neurogenic programme, including differentiation and migration. Much of that activity is due to NeuroD1 acting as a pioneer factor. NeuroD1 is able to bind its targets within repressive chromatin and can induce a more open chromatin state amenable...
Source: EMBO Journal - January 3, 2016 Category: Molecular Biology Authors: Glahs, A., Zinzen, R. P. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Neuroscience, Transcription News [amp ] Views Source Type: research

Protein localisation by electron microscopy reveals the architecture of the yeast spliceosomal B complex
The spliceosome assembles on a pre-mRNA intron by binding of five snRNPs and numerous proteins, leading to the formation of the pre-catalytic B complex. While the general morphology of the B complex is known, the spatial arrangement of proteins and snRNP subunits within it remain to be elucidated. To shed light on the architecture of the yeast B complex, we immuno-labelled selected proteins and located them by negative-stain electron microscopy. The B complex exhibited a triangular shape with main body, head and neck domains. We located the U5 snRNP components Brr2 at the top and Prp8 and Snu114 in the centre of the main b...
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Rigo, N., Sun, C., Fabrizio, P., Kastner, B., Lührmann, R. Tags: RNA Biology, Structural Biology Articles Source Type: research

Molecular architecture of the ribosome-bound Hepatitis C Virus internal ribosomal entry site RNA
Internal ribosomal entry sites (IRESs) are structured cis-acting RNAs that drive an alternative, cap-independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo-EM reconstructions of the ribosome 80S- and 40S-bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S•HCV IRES complex reveals dynamic conformational modes of...
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Yamamoto, H., Collier, M., Loerke, J., Ismer, J., Schmidt, A., Hilal, T., Sprink, T., Yamamoto, K., Mielke, T., Bürger, J., Shaikh, T. R., Dabrowski, M., Hildebrand, P. W., Scheerer, P., Spahn, C. M. Tags: Protein Biosynthesis & Quality Control, Structural Biology Articles Source Type: research

Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity
In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion-like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans-synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient ne...
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Wegmann, S., Maury, E. A., Kirk, M. J., Saqran, L., Roe, A., DeVos, S. L., Nicholls, S., Fan, Z., Takeda, S., Cagsal-Getkin, O., William, C. M., Spires-Jones, T. L., Pitstick, R., Carlson, G. A., Pooler, A. M., Hyman, B. T. Tags: Neuroscience Articles Source Type: research

tRNA processing defects induce replication stress and Chk2-dependent disruption of piRNA transcription
RNase P is a conserved endonuclease that processes the 5' trailer of tRNA precursors. We have isolated mutations in Rpp30, a subunit of RNase P, and find that these induce complete sterility in Drosophila females. Here, we show that sterility is not due to a shortage of mature tRNAs, but that atrophied ovaries result from the activation of several DNA damage checkpoint proteins, including p53, Claspin, and Chk2. Indeed, we find that tRNA processing defects lead to increased replication stress and de-repression of transposable elements in mutant ovaries. We also report that transcription of major piRNA sources collapse in m...
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Molla-Herman, A., Valles, A. M., Ganem-Elbaz, C., Antoniewski, C., Huynh, J.-R. Tags: Development & Differentiation, DNA Replication, Repair & Recombination, RNA Biology Articles Source Type: research

Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs
Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption ...
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Planells-Cases, R., Lutter, D., Guyader, C., Gerhards, N. M., Ullrich, F., Elger, D. A., Kucukosmanoglu, A., Xu, G., Voss, F. K., Reincke, S. M., Stauber, T., Blomen, V. A., Vis, D. J., Wessels, L. F., Brummelkamp, T. R., Borst, P., Rottenberg, S., Jentsc Tags: Cancer, Autophagy & Cell Death, Membrane & Intracellular Transport Articles Source Type: research

No full admission for tau to the exclusive prion club yet
Aggregation of the microtubule-associated protein tau is a key feature of Alzheimer's disease and other so-called tauopathies, yet what causes this protein to aggregate and what renders it toxic is only slowly being revealed. Because tau spreads in a stereotypical pattern through the diseased brain, it has been proposed that it possesses prion-like properties, with aggregation-prone tau facilitating the conversion of "naìˆve" tau into "toxic" forms. The current study by Wegmann et al (2015) addresses whether tau fulfils classical "prion criteria" by assessing its spreading and toxicity i...
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Polanco, J. C., Götz, J. Tags: Neuroscience News [amp ] Views Source Type: research

Misprocessed tRNA response targets piRNA clusters
Germline PIWI-interacting RNA (piRNA) clusters have a characteristic transcriptional status; although they do not have their own promoters, both genomic strands are transcribed, while splicing and 3' processing signals are neglected. How this transcription is maintained remains unknown. Molla-Herman et al (2015) discovered that mutations in a tRNA processing factor cause the loss of transcription at some piRNA clusters, leading to sterility in Drosophila melanogaster. This defect in piRNA cluster transcription is restored by mutations in genes required for the DNA damage checkpoint or replication. (Source: EMBO Journal)
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Yamanaka, S., Siomi, H. Tags: Development & Differentiation, DNA Replication, Repair & Recombination, RNA Biology News [amp ] Views Source Type: research

VRACs swallow platinum drugs
Platinum-based drugs such as cisplatin and carboplatin are on the WHO model list of essential medicines, as highly effective chemotherapeutic drugs for the treatment of various solid tumors. These drugs react with purine residues in DNA, thereby causing DNA damage, inhibition of cell division, and eventually cell death. However, the mechanisms whereby platinum-based drugs enter cancer cells remained poorly understood. In this issue, Planells-Cases et al (2015) provide evidence that cells take up cisplatin and carboplatin via volume-regulated anion channels (VRACs), more specifically VRACs composed of LRRC8A and LRRC8D...
Source: EMBO Journal - December 14, 2015 Category: Molecular Biology Authors: Voets, T., Nilius, B., Vennekens, R. Tags: Cancer, Autophagy & Cell Death, Membrane & Intracellular Transport News [amp ] Views Source Type: research

Oct4-induced oligodendrocyte progenitor cells enhance functional recovery in spinal cord injury model
This study provides a simple strategy to generate functional self-renewing iOPCs and yields insights for the in-depth study of demyelination and regenerative medicine. (Source: EMBO Journal)
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Kim, J. B., Lee, H., Arauzo-Bravo, M. J., Hwang, K., Nam, D., Park, M. R., Zaehres, H., Park, K. I., Lee, S.-J. Tags: Neuroscience, Stem Cells Articles Source Type: research

EglN2 associates with the NRF1-PGC1{alpha} complex and controls mitochondrial function in breast cancer
The EglN2/PHD1 prolyl hydroxylase is an important oxygen sensor contributing to breast tumorigenesis. Emerging studies suggest that there is functional cross talk between oxygen sensing and mitochondrial function, both of which play an essential role for sustained tumor growth. However, the potential link between EglN2 and mitochondrial function remains largely undefined. Here, we show that EglN2 depletion decreases mitochondrial respiration in breast cancer under normoxia and hypoxia, which correlates with decreased mitochondrial DNA in a HIF1/2α-independent manner. Integrative analyses of gene expression profile an...
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Zhang, J., Wang, C., Chen, X., Takada, M., Fan, C., Zheng, X., Wen, H., Liu, Y., Wang, C., Pestell, R. G., Aird, K. M., Kaelin, W. G., Liu, X. S., Zhang, Q. Tags: Cancer, Metabolism, Transcription Articles Source Type: research

Unexpected features and mechanism of heterodimer formation of a herpesvirus nuclear egress complex
Herpesvirus nucleocapsids escape from the nucleus in a process orchestrated by a highly conserved, viral nuclear egress complex. In human cytomegalovirus, the complex consists of two proteins, UL50 and UL53. We solved structures of versions of UL53 and the complex by X-ray crystallography. The UL53 structures, determined at 1.93 and 3.0 Å resolution, contained unexpected features including a Bergerat fold resembling that found in certain nucleotide-binding proteins, and a Cys3His zinc finger. Substitutions of zinc-coordinating residues decreased UL50–UL53 co-localization in transfected cells, and, when incorpor...
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Lye, M. F., Sharma, M., El Omari, K., Filman, D. J., Schuermann, J. P., Hogle, J. M., Coen, D. M. Tags: Microbiology, Virology & Host Pathogen Interaction, Structural Biology Articles Source Type: research

Structural basis of membrane budding by the nuclear egress complex of herpesviruses
During nuclear egress, herpesvirus capsids bud at the inner nuclear membrane forming perinuclear viral particles that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytoplasm. This unusual budding process is mediated by the nuclear egress complex (NEC) composed of two conserved viral proteins, UL31 and UL34. Earlier, we discovered that the herpesvirus nuclear egress complex (NEC) could bud synthetic membranes in vitro without the help of other proteins by forming a coat-like hexagonal scaffold inside the budding membrane. To understand the structural basis of NEC-mediated membrane buddin...
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Bigalke, J. M., Heldwein, E. E. Tags: Microbiology, Virology & Host Pathogen Interaction, Structural Biology Articles Source Type: research

A non-canonical role of the p97 complex in RIG-I antiviral signaling
RIG-I is a well-studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. Viral infection significantly strengthens the interaction between RIG-I and the p97 complex by ...
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Hao, Q., Jiao, S., Shi, Z., Li, C., Meng, X., Zhang, Z., Wang, Y., Song, X., Wang, W., Zhang, R., Zhao, Y., Wong, C. C., Zhou, Z. Tags: Immunology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research

The Mediator subunit MED23 couples H2B mono-ubiquitination to transcriptional control and cell fate determination
The Mediator complex orchestrates multiple transcription factors with the Pol II apparatus for precise transcriptional control. However, its interplay with the surrounding chromatin remains poorly understood. Here, we analyze differential histone modifications between WT and MED23–/– (KO) cells and identify H2B mono-ubiquitination at lysine 120 (H2Bub) as a MED23-dependent histone modification. Using tandem affinity purification and mass spectrometry, we find that MED23 associates with the RNF20/40 complex, the enzyme for H2Bub, and show that this association is critical for the recruitment of RNF20/40 to chrom...
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Yao, X., Tang, Z., Fu, X., Yin, J., Liang, Y., Li, C., Li, H., Tian, Q., Roeder, R. G., Wang, G. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Post-translational Modifications, Proteolysis & Proteomics, Transcription Articles Source Type: research

Long non-coding RNAs in corticogenesis: deciphering the non-coding code of the brain
Evidence on the role of long non-coding (lnc) RNAs has been accumulating over decades, but it has been only recently that advances in sequencing technologies have allowed the field to fully appreciate their abundance and diversity. Despite this, only a handful of lncRNAs have been phenotypically or mechanistically studied. Moreover, novel lncRNAs and new classes of RNAs are being discovered at growing pace, suggesting that this class of molecules may have functions as diverse as protein-coding genes. Interestingly, the brain is the organ where lncRNAs have the most peculiar features including the highest number of lncRNAs ...
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Aprea, J., Calegari, F. Tags: Neuroscience, RNA Biology Review Source Type: research

MED23: a new Mediator of H2B monoubiquitylation
The Mediator multiprotein complex physically links transcription factors to RNA polymerase II and the basal transcription machinery. While the Mediator complex has been shown to be required for transcriptional initiation and elongation, the understanding of its interplay with histone modifying enzymes and post-translational modifications remains elusive. In this issue of The EMBO Journal, Yao et al (2015) report that the MED23 subunit of the Mediator complex physically associates with the heterodimeric RNF20/40 E3-ligase complex to facilitate the monoubiquitylation of histone H2B on gene bodies of actively transcribed...
Source: EMBO Journal - December 2, 2015 Category: Molecular Biology Authors: Streubel, G., Bracken, A. P. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Post-translational Modifications, Proteolysis & Proteomics, Transcription News [amp ] Views Source Type: research

The cis-regulatory code of Hox function in Drosophila
(Source: EMBO Journal)
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Sorge, S., Ha, N., Polychronidou, M., Friedrich, J., Bezdan, D., Kaspar, P., Schaefer, M. H., Ossowski, S., Henz, S. R., Mundorf, J., Rätzer, J., Papagiannouli, F., Lohmann, I. Tags: Corrigendum Source Type: research

Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1
Mutations in the PTEN-induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser65) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1-dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaf...
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Lai, Y.-C., Kondapalli, C., Lehneck, R., Procter, J. B., Dill, B. D., Woodroof, H. I., Gourlay, R., Peggie, M., Macartney, T. J., Corti, O., Corvol, J.-C., Campbell, D. G., Itzen, A., Trost, M., Muqit, M. M. Tags: Membrane & Intracellular Transport, Methods & Resources, Post-translational Modifications, Proteolysis & Proteomics Source Type: research

Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction
This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies. (Source: EMBO Journal)
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Ben-Gedalya, T., Moll, L., Bejerano-Sagie, M., Frere, S., Cabral, W. A., Friedmann-Morvinski, D., Slutsky, I., Burstyn-Cohen, T., Marini, J. C., Cohen, E. Tags: Molecular Biology of Disease, Neuroscience Articles Source Type: research

The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes
Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator Id3 decreased the number of astrocytes generated from SVZ-derived adult NSPCs in the cortical lesion area after traumatic br...
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Bohrer, C., Pfurr, S., Mammadzada, K., Schildge, S., Plappert, L., Hils, M., Pous, L., Rauch, K. S., Dumit, V. I., Pfeifer, D., Dengjel, J., Kirsch, M., Schachtrup, K., Schachtrup, C. Tags: Neuroscience Articles Source Type: research

H3K9 methylation extends across natural boundaries of heterochromatin in the absence of an HP1 protein
Proteins of the conserved HP1 family are elementary components of heterochromatin and are generally assumed to play a central role in the creation of a rigid, densely packed heterochromatic network that is inaccessible to the transcription machinery. Here, we demonstrate that the fission yeast HP1 protein Swi6 exists as a single highly dynamic population that rapidly exchanges in cis and in trans between different heterochromatic regions. Binding to methylated H3K9 or to heterochromatic RNA decelerates Swi6 mobility. We further show that Swi6 is largely dispensable to the maintenance of heterochromatin domains. In the abse...
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Stunnenberg, R., Kulasegaran-Shylini, R., Keller, C., Kirschmann, M. A., Gelman, L., Bühler, M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Transcription Articles Source Type: research

Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14
The intracellular chaperone heat-shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig-superfamily lectins on mammalian leukocytes that recognize sialic acid-bearing glycans and thereby modulate immune responses. Siglec-5 and Siglec-14, expressed on monocytes and neutrophils, share identical ligand-binding domains but have opposing signaling functions. Based...
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Fong, J. J., Sreedhara, K., Deng, L., Varki, N. M., Angata, T., Liu, Q., Nizet, V., Varki, A. Tags: Immunology Articles Source Type: research

Alu element-containing RNAs maintain nucleolar structure and function
Non-coding RNAs play a key role in organizing the nucleus into functional subcompartments. By combining fluorescence microscopy and RNA deep-sequencing-based analysis, we found that RNA polymerase II transcripts originating from intronic Alu elements (aluRNAs) were enriched in the nucleolus. Antisense-oligo-mediated depletion of aluRNAs or drug-induced inhibition of RNA polymerase II activity disrupted nucleolar structure and impaired RNA polymerase I-dependent transcription of rRNA genes. In contrast, overexpression of a prototypic aluRNA sequence increased both nucleolus size and levels of pre-rRNA, suggesting a function...
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Caudron-Herger, M., Pankert, T., Seiler, J., Nemeth, A., Voit, R., Grummt, I., Rippe, K. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, RNA Biology, Transcription Articles Source Type: research

Complement activation, regulation, and molecular basis for complement-related diseases
We present an integrated and updated view of complement based on structural and functional data and describe the new roles attributed to complement. Finally, we discuss how the structural and mechanistic understanding of the complement system rationalizes the genetic defects conferring uncontrolled activation or other undesirable effects of complement. (Source: EMBO Journal)
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Bajic, G., Degn, S. E., Thiel, S., Andersen, G. R. Tags: Immunology Review Source Type: research

Siglecs take a TOLL on inflammation: deciphering the Hsp70 riddle
The manuscript by Fong et al (2015) in this issue of The EMBO Journal addresses an ongoing question in immunology: are extracellular HSPs endogenous inflammatory signals or are they in fact built-in inhibitors of those same functions? In a highly original series of experiments, they identify novel Hsp70 receptors in monocytes as members of the Siglec family. Even more significantly, two Siglec family members transmitted divergent responses to Hsp70, with Siglec-5 dampening inflammation while Siglec-14 triggering the inflammatory cascade. These findings therefore go some way in addressing the open question: is Hsp70 pr...
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Calderwood, S. K., Murshid, A. Tags: Immunology News [amp ] Views Source Type: research

Assembly of the nucleolus: in need of revision
Our current view of the nucleolus has been shaped by the concept that the organization of this prominent compartment within the nucleus is primarily dictated by its function, the making of ribosome subunits. Whether ribosome biogenesis is framed by a dedicated nucleolar scaffold has remained unclear. In this issue of The EMBO Journal, Caudron-Herger and colleagues present evidence for a nucleolar skeleton composed of non-coding RNA enriched in Alu repeat elements. (Source: EMBO Journal)
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Carmo-Fonseca, M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, RNA Biology, Transcription News [amp ] Views Source Type: research

Statistical relevance--relevant statistics, part I
(Source: EMBO Journal)
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Klaus, B. Tags: Commentary Source Type: research

Gottfried Schatz (1936-2015)--mitochondrial pioneer and ambassador for science
(Source: EMBO Journal)
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Haucke, V., Glick, B. S. Tags: Obituary Source Type: research

Reproducibility blues
Research findings advance science only if they are significant, reliable and reproducible. Scientists and journals must publish robust data in a way that renders it optimally reproducible. Reproducibility has to be incentivized and supported by the research infrastructure but without dampening innovation. (Source: EMBO Journal)
Source: EMBO Journal - November 12, 2015 Category: Molecular Biology Authors: Pulverer, B. Tags: Editorial Source Type: research

Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling
Degradation of mitochondria via selective autophagy, termed mitophagy, contributes to mitochondrial quality and quantity control whose defects have been implicated in oxidative phosphorylation deficiency, aberrant cell differentiation, and neurodegeneration. How mitophagy is regulated in response to cellular physiology remains obscure. Here, we show that mitophagy in yeast is linked to the phospholipid biosynthesis pathway for conversion of phosphatidylethanolamine to phosphatidylcholine by the two methyltransferases Cho2 and Opi3. Under mitophagy-inducing conditions, cells lacking Opi3 exhibit retardation of Cho2 repressi...
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Sakakibara, K., Eiyama, A., Suzuki, S. W., Sakoh-Nakatogawa, M., Okumura, N., Tani, M., Hashimoto, A., Nagumo, S., Kondo-Okamoto, N., Kondo-Kakuta, C., Asai, E., Kirisako, H., Nakatogawa, H., Kuge, O., Takao, T., Ohsumi, Y., Okamoto, K. Tags: Autophagy & Cell Death, Metabolism, Physiology Articles Source Type: research

Disruption of adaptor protein 2{mu} (AP-2{mu}) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing
Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2μ (AP-2μ) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2μ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspi...
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Jung, S., Maritzen, T., Wichmann, C., Jing, Z., Neef, A., Revelo, N. H., Al-Moyed, H., Meese, S., Wojcik, S. M., Panou, I., Bulut, H., Schu, P., Ficner, R., Reisinger, E., Rizzoli, S. O., Neef, J., Strenzke, N., Haucke, V., Moser, T. Tags: Neuroscience Articles Source Type: research

Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma
Glucose metabolic reprogramming is a hallmark of cancer. Cancer cells rapidly adjust their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate in a hypoxic environment, but the mechanism underlying this switch is still incompletely understood. Here, we report that hypoxia potently induces the RNA-binding protein HuR to specifically bind primary miR-199a transcript to block miR-199a maturation in hepatocellular carcinoma (HCC) cells. We demonstrate that this hypoxia-suppressed miR-199a plays a decisive role in limiting glycolysis in HCC cells by targeting hexokinase-2 (H...
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Zhang, L.-F., Lou, J.-T., Lu, M.-H., Gao, C., Zhao, S., Li, B., Liang, S., Li, Y., Li, D., Liu, M.-F. Tags: Cancer, Metabolism, RNA Biology Articles Source Type: research

Distinct preoptic-BST nuclei dissociate paternal and infanticidal behavior in mice
Paternal behavior is not innate but arises through social experience. After mating and becoming fathers, male mice change their behavior toward pups from infanticide to paternal care. However, the precise brain areas and circuit mechanisms connecting these social behaviors are largely unknown. Here we demonstrated that the c-Fos expression pattern in the four nuclei of the preoptic-bed nuclei of stria terminalis (BST) region could robustly discriminate five kinds of previous social behavior of male mice (parenting, infanticide, mating, inter-male aggression, solitary control). Specifically, neuronal activation in the centr...
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Tsuneoka, Y., Tokita, K., Yoshihara, C., Amano, T., Esposito, G., Huang, A. J., Yu, L. M., Odaka, Y., Shinozuka, K., McHugh, T. J., Kuroda, K. O. Tags: Neuroscience Articles Source Type: research

Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS
Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule for...
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Emde, A., Eitan, C., Liou, L.-L., Libby, R. T., Rivkin, N., Magen, I., Reichenstein, I., Oppenheim, H., Eilam, R., Silvestroni, A., Alajajian, B., Ben-Dov, I. Z., Aebischer, J., Savidor, A., Levin, Y., Sons, R., Hammond, S. M., Ravits, J. M., Möll Tags: Neuroscience, RNA Biology Articles Source Type: research

Analysis of acetylation stoichiometry suggests that SIRT3 repairs nonenzymatic acetylation lesions
Acetylation is frequently detected on mitochondrial enzymes, and the sirtuin deacetylase SIRT3 is thought to regulate metabolism by deacetylating mitochondrial proteins. However, the stoichiometry of acetylation has not been studied and is important for understanding whether SIRT3 regulates or suppresses acetylation. Using quantitative mass spectrometry, we measured acetylation stoichiometry in mouse liver tissue and found that SIRT3 suppressed acetylation to a very low stoichiometry at its target sites. By examining acetylation changes in the liver, heart, brain, and brown adipose tissue of fasted mice, we found that SIRT...
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Weinert, B. T., Moustafa, T., Iesmantavicius, V., Zechner, R., Choudhary, C. Tags: Metabolism, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research

NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity
The SMC5/6 complex is the least understood of SMC complexes. In yeast, smc5/6 mutants phenocopy mutations in sgs1, the BLM ortholog that is deficient in Bloom's syndrome (BS). We here show that NSMCE2 (Mms21, in Saccharomyces cerevisiae), an essential SUMO ligase of the SMC5/6 complex, suppresses cancer and aging in mice. Surprisingly, a mutation that compromises NSMCE2-dependent SUMOylation does not have a detectable impact on murine lifespan. In contrast, NSMCE2 deletion in adult mice leads to pathologies resembling those found in patients of BS. Moreover, and whereas NSMCE2 deletion does not have a detectable impact on ...
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Jacome, A., Gutierrez-Martinez, P., Schiavoni, F., Tenaglia, E., Martinez, P., Rodriguez-Acebes, S., Lecona, E., Murga, M., Mendez, J., Blasco, M. A., Fernandez-Capetillo, O. Tags: DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research

MicroRNAs in ALS: small pieces to the puzzle
MicroRNAs have emerged as crucial regulators of neuronal function, suggesting that aberrant microRNA expression might contribute to pathologies of the nervous system. In this issue of The EMBO Journal, Emde et al (2015) report a global decrease in microRNAs as common hallmark of different forms of amyotrophic lateral sclerosis (ALS). Strikingly, enhancing microRNA biogenesis has beneficial effects on the neuromuscular function in mouse models of ALS. Thus, the microRNA pathway represents a promising novel target for therapeutic intervention in neurodegeneration. (Source: EMBO Journal)
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Bicker, S., Schratt, G. Tags: Neuroscience, RNA Biology News [amp ] Views Source Type: research

Acetyl-ed question in mitochondrial biology?
Lysine acetylation on numerous mitochondrial proteins, targeted by the sirtuin deacylase SIRT3, has been proposed to play a major role in regulating diverse mitochondrial functions, particularly in the liver. A new study by Weinert, Choudhary, and colleagues, in this issue of The EMBO Journal, finds that the absolute levels of hepatic mitochondrial protein acetylation in wild-type mice are extremely low and may be insufficient to exert regulatory effects. (Source: EMBO Journal)
Source: EMBO Journal - November 3, 2015 Category: Molecular Biology Authors: Lombard, D. B., Dash, B. P., Kumar, S. Tags: Metabolism, Post-translational Modifications, Proteolysis & Proteomics News [amp ] Views Source Type: research

Retraction: 'An endogenous, systemic RNAi pathway in plants'
(Source: EMBO Journal)
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Dunoyer, P., Brosnan, C. A., Schott, G., Wang, Y., Jay, F., Alioua, A., Himber, C., Voinnet, O. Tags: Retractions Source Type: research

Retraction: 'Viral pathogenicity determinants are suppressors of transgene silencing in Nicotiana benthamiana'
(Source: EMBO Journal)
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Brigneti, G., Voinnet, O., Li, W.-X., Ji, L.-H., Ding, S.-W., Baulcombe, D. C. Tags: Retractions Source Type: research

Differential effects of viral silencing suppressors on siRNA and miRNA loading support the existence of two distinct cellular pools of ARGONAUTE1
(Source: EMBO Journal)
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Schott, G., Mari-Ordonez, A., Himber, C., Alioua, A., Voinnet, O., Dunoyer, P. Tags: Corrigenda Source Type: research

Nuclear import of CaMV P6 is required for infection and suppression of the RNA silencing factor DRB4
(Source: EMBO Journal)
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Haas, G., Azevedo, J., Moissiard, G., Geldreich, A., Himber, C., Bureau, M., Fukuhara, T., Keller, M., Voinnet, O. Tags: Corrigenda Source Type: research

Two classes of short interfering RNA in RNA silencing
(Source: EMBO Journal)
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Hamilton, A., Voinnet, O., Chappell, L., Baulcombe, D. Tags: Corrigenda Source Type: research

Postmitotic diversification of olfactory neuron types is mediated by differential activities of the HMG-box transcription factor SOX-2
Diversification of neuron classes is essential for functions of the olfactory system, but the underlying mechanisms that generate individual olfactory neuron types are only beginning to be understood. Here we describe a role of the highly conserved HMG-box transcription factor SOX-2 in postmitotic specification and alternative differentiation of the Caenorhabditis elegans AWC and AWB olfactory neurons. We show that SOX-2 partners with different transcription factors to diversify postmitotic olfactory cell types. SOX-2 functions cooperatively with the OTX/OTD transcription factor CEH-36 to specify an AWC "ground state,...
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Alqadah, A., Hsieh, Y.-W., Vidal, B., Chang, C., Hobert, O., Chuang, C.-F. Tags: Development & Differentiation, Transcription Articles Source Type: research

Alternative Hfq-sRNA interaction modes dictate alternative mRNA recognition
Many bacteria use small RNAs (sRNAs) and the RNA chaperone Hfq to regulate mRNA stability and translation. Hfq, a ring-shaped homohexamer, has multiple faces that can bind both sRNAs and their mRNA targets. We find that Hfq has at least two distinct ways in which it interacts with sRNAs; these different binding properties have strong effects on the stability of the sRNA in vivo and the sequence requirements of regulated mRNAs. Class I sRNAs depend on proximal and rim Hfq sites for stability and turn over rapidly. Class II sRNAs are more stable and depend on the proximal and distal Hfq sites for stabilization. Using de...
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Schu, D. J., Zhang, A., Gottesman, S., Storz, G. Tags: Microbiology, Virology & Host Pathogen Interaction, RNA Biology Articles Source Type: research

Formation of the transition zone by Mks5/Rpgrip1L establishes a ciliary zone of exclusion (CIZE) that compartmentalises ciliary signalling proteins and controls PIP2 ciliary abundance
Cilia are thought to harbour a membrane diffusion barrier within their transition zone (TZ) that compartmentalises signalling proteins. How this "ciliary gate" assembles and functions remains largely unknown. Contrary to current models, we present evidence that Caenorhabditis elegans MKS-5 (orthologue of mammalian Mks5/Rpgrip1L/Nphp8 and Rpgrip1) may not be a simple structural scaffold for anchoring> 10 different proteins at the TZ, but instead, functions as an assembly factor. This activity is needed to form TZ ultrastructure, which comprises Y-shaped axoneme-to-membrane connectors. Coiled-coil and C2 do...
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Jensen, V. L., Li, C., Bowie, R. V., Clarke, L., Mohan, S., Blacque, O. E., Leroux, M. R. Tags: Cell Adhesion, Polarity & Cytoskeleton Articles Source Type: research

Notch signaling regulates gastric antral LGR5 stem cell function
The major signaling pathways regulating gastric stem cells are unknown. Here we report that Notch signaling is essential for homeostasis of LGR5+ antral stem cells. Pathway inhibition reduced proliferation of gastric stem and progenitor cells, while activation increased proliferation. Notch dysregulation also altered differentiation, with inhibition inducing mucous and endocrine cell differentiation while activation reduced differentiation. Analysis of gastric organoids demonstrated that Notch signaling was intrinsic to the epithelium and regulated growth. Furthermore, in vivo Notch manipulation affected the efficienc...
Source: EMBO Journal - October 14, 2015 Category: Molecular Biology Authors: Demitrack, E. S., Gifford, G. B., Keeley, T. M., Carulli, A. J., VanDussen, K. L., Thomas, D., Giordano, T. J., Liu, Z., Kopan, R., Samuelson, L. C. Tags: Development & Differentiation Articles Source Type: research