RNA editing of Filamin A pre-mRNA regulates vascular contraction and diastolic blood pressure
Epitranscriptomic events such as adenosine-to-inosine (A-to-I) RNA editing by ADAR can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin crosslinking protein Filamin A (FLNA) mediates a Q-to-R transition in the interactive C-terminal region. While FLNA editing is conserved among vertebrates, its physiological function remains unclear. Here, we show that cardiovascular tissues in humans and mice show massive editing and that FLNA RNA is the most prominent substrate. Patient-derived RNA-Seq data demonstrate a significant drop in FLNA editing associated with cardiovascular diseases. Using mice w...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Jain, M., Mann, T. D., Stulic, M., Rao, S. P., Kirsch, A., Pullirsch, D., Strobl, X., Rath, C., Reissig, L., Moreth, K., Klein-Rodewald, T., Bekeredjian, R., Gailus-Durner, V., Fuchs, H., Hrabe de Angelis, M., Pablik, E., Cimatti, L., Martin, D., Zinnanti Tags: Development & Differentiation, RNA Biology, Vascular Biology & Angiogenesis Articles Source Type: research
Queuing up the ribosome: nutrition and the microbiome control protein synthesis
The health of an organism is intricately linked to its gut microbiome. However, the mechanisms by which the microbiome affect the host gene regulation are still not well established. A new study by Tuorto et al (2018) shows that queuine, a nitrogenous base obtained from the gut microbiota, is used to modify tRNAs and affects cellular behavior. Dietary queuine is required for proper protein synthesis, and its depletion activates cellular stress responses in vitro and in vivo. (Source: EMBO Journal)
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Kozlovski, I., Agami, R. Tags: Metabolism, Protein Biosynthesis & Quality Control, RNA Biology News [amp ] Views Source Type: research
SHLD2/FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice
DNA double-strand breaks (DSBs) can be repaired by two major pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). DNA repair pathway choice is governed by the opposing activities of 53BP1, in complex with its effectors RIF1 and REV7, and BRCA1. However, it remains unknown how the 53BP1/RIF1/REV7 complex stimulates NHEJ and restricts HR to the S/G2 phases of the cell cycle. Using a mass spectrometry (MS)-based approach, we identify 11 high-confidence REV7 interactors and elucidate the role of SHLD2 (previously annotated as FAM35A and RINN2) as an effector of REV7 in the NHEJ pathway. FAM35A depleti...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Findlay, S., Heath, J., Luo, V. M., Malina, A., Morin, T., Coulombe, Y., Djerir, B., Li, Z., Samiei, A., Simo-Cheyou, E., Karam, M., Bagci, H., Rahat, D., Grapton, D., Lavoie, E. G., Dove, C., Khaled, H., Kuasne, H., Mann, K. K., Klein, K. O., Greenwood, Tags: DNA Replication, Repair & Recombination Articles Source Type: research
Queuosine-modified tRNAs confer nutritional control of protein translation
Global protein translation as well as translation at the codon level can be regulated by tRNA modifications. In eukaryotes, levels of tRNA queuosinylation reflect the bioavailability of the precursor queuine, which is salvaged from the diet and gut microbiota. We show here that nutritionally determined Q-tRNA levels promote Dnmt2-mediated methylation of tRNA Asp and control translational speed of Q-decoded codons as well as at near-cognate codons. Deregulation of translation upon queuine depletion results in unfolded proteins that trigger endoplasmic reticulum stress and activation of the unfolded protein response, both in...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Tuorto, F., Legrand, C., Cirzi, C., Federico, G., Liebers, R., Müller, M., Ehrenhofer-Murray, A. E., Dittmar, G., Gröne, H.-J., Lyko, F. Tags: Metabolism, Protein Biosynthesis & Quality Control, RNA Biology Articles Source Type: research
Deficiency in the nuclear long noncoding RNA Charme causes myogenic defects and heart remodeling in mice
Myogenesis is a highly regulated process that involves the conversion of progenitor cells into multinucleated myofibers. Besides proteins and miRNAs, long noncoding RNAs (lncRNAs) have been shown to participate in myogenic regulatory circuitries. Here, we characterize a murine chromatin-associated muscle-specific lncRNA, Charme, which contributes to the robustness of the myogenic program in vitro and in vivo. In myocytes, Charme depletion triggers the disassembly of a specific chromosomal domain and the downregulation of myogenic genes contained therein. Notably, several Charme-sensitive genes are associated...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Ballarino, M., Cipriano, A., Tita, R., Santini, T., Desideri, F., Morlando, M., Colantoni, A., Carrieri, C., Nicoletti, C., Musaro, A., Carroll, D. O., Bozzoni, I. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, RNA Biology, Vascular Biology & Angiogenesis Articles Source Type: research
Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS1-caspase-1 axis
Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon (IFN) signaling and inflammasomes. Here, we report that Zika virus (ZIKV) infection triggers NLRP3 inflammasome activation, which is further enhanced by viral non-structural protein NS1 to benefit its replication. NS1 recruits the host deubiquitinase USP8 to cleave K11-linked poly-ubiquitin chains from caspase-1 at Lys134, thus inhibiting the proteasomal degradation of caspase-1. The enhanced stabilization of caspase-1 by NS1 promotes the cleavage of cGAS, which recognizes mitochondrial DNA release and initiat...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Zheng, Y., Liu, Q., Wu, Y., Ma, L., Zhang, Z., Liu, T., Jin, S., She, Y., Li, Y.-P., Cui, J. Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
One-step CRISPR/Cas9 method for the rapid generation of human antibody heavy chain knock-in mice
Here, we describe a one-step, in vivo CRISPR/Cas9 nuclease-mediated strategy to generate knock-in mice. We produced knock-in (KI) mice wherein a 1.9-kb DNA fragment bearing a pre-arranged human B-cell receptor heavy chain was recombined into the native murine immunoglobulin locus. Our methodology relies on Cas9 nuclease-induced double-stranded breaks directed by two sgRNAs to occur within the specific target locus of fertilized oocytes. These double-stranded breaks are subsequently repaired via homology-directed repair by a plasmid-borne template containing the pre-arranged human immunoglobulin heavy chain. To validat...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Lin, Y.-C., Pecetta, S., Steichen, J. M., Kratochvil, S., Melzi, E., Arnold, J., Dougan, S. K., Wu, L., Kirsch, K. H., Nair, U., Schief, W. R., Batista, F. D. Tags: Genetics, Gene Therapy & Genetic Disease, Immunology Resource Source Type: research
DCAF13 promotes pluripotency by negatively regulating SUV39H1 stability during early embryonic development
Mammalian oocytes and zygotes have the unique ability to reprogram a somatic cell nucleus into a totipotent state. SUV39H1/2-mediated histone H3 lysine-9 trimethylation (H3K9me3) is a major barrier to efficient reprogramming. How SUV39H1/2 activities are regulated in early embryos and during generation of induced pluripotent stem cells (iPSCs) remains unclear. Since expression of the CRL4 E3 ubiquitin ligase in oocytes is crucial for female fertility, we analyzed putative CRL4 adaptors (DCAFs) and identified DCAF13 as a novel CRL4 adaptor that is essential for preimplantation embryonic development. Dcaf13 is expressed from...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Zhang, Y.-L., Zhao, L.-W., Zhang, J., Le, R., Ji, S.-Y., Chen, C., Gao, Y., Li, D., Gao, S., Fan, H.-Y. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, Stem Cells Articles Source Type: research
Parkinson's disease: convergence on synaptic homeostasis
Parkinson's disease, the second most common neurodegenerative disorder, affects millions of people globally. There is no cure, and its prevalence will double by 2030. In recent years, numerous causative genes and risk factors for Parkinson's disease have been identified and more than half appear to function at the synapse. Subtle synaptic defects are thought to precede blunt neuronal death, but the mechanisms that are dysfunctional at synapses are only now being unraveled. Here, we review recent work and propose a model where different Parkinson proteins interact in a cell compartment-specific manner at the synapse where t...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Soukup, S.-F., Vanhauwaert, R., Verstreken, P. Tags: Molecular Biology of Disease, Neuroscience Review Source Type: research
Error-free DNA damage tolerance pathway is facilitated by the Irc5 translocase through cohesin
DNA damage tolerance (DDT) mechanisms facilitate replication resumption and completion when DNA replication is blocked by bulky DNA lesions. In budding yeast, template switching (TS) via the Rad18/Rad5 pathway is a favored DDT pathway that involves usage of the sister chromatid as a template to bypass DNA lesions in an error-free recombination-like process. Here, we establish that the Snf2 family translocase Irc5 is a novel factor that promotes TS and averts single-stranded DNA persistence during replication. We demonstrate that, during replication stress, Irc5 enables replication progression by assisting enrichment of coh...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Litwin, I., Bakowski, T., Szakal, B., Pilarczyk, E., Maciaszczyk-Dziubinska, E., Branzei, D., Wysocki, R. Tags: Cell Cycle, DNA Replication, Repair & Recombination Articles Source Type: research
TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy
Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress-induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62-NRF2 axis. We show that TRIM16 is an integral part of the p62-KEAP1-NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2. Under ...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Jena, K. K., Kolapalli, S. P., Mehto, S., Nath, P., Das, B., Sahoo, P. K., Ahad, A., Syed, G. H., Raghav, S. K., Senapati, S., Chauhan, S., Chauhan, S. Tags: Autophagy & Cell Death, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling
Multi-subunit cullin-RING ligases (CRLs) are the largest family of ubiquitin E3 ligases in humans. CRL activity is tightly regulated to prevent unintended substrate degradation or autocatalytic degradation of CRL subunits. Using a proteomics strategy, we discovered that CRL4AMBRA1 (CRL substrate receptor denoted in superscript) targets Elongin C (ELOC), the essential adapter protein of CRL5 complexes, for polyubiquitination and degradation. We showed that the ubiquitin ligase function of CRL4AMBRA1 is required to disrupt the assembly and attenuate the ligase activity of human CRL5SOCS3 and HIV-1 CRL5VIF complexes as AMBRA1...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Chen, S.-H., Jang, G. M., Hüttenhain, R., Gordon, D. E., Du, D., Newton, B. W., Johnson, J. R., Hiatt, J., Hultquist, J. F., Johnson, T. L., Liu, Y.-L., Burton, L. A., Ye, J., Reichermeier, K. M., Stroud, R. M., Marson, A., Debnath, J., Gross, J. Tags: Autophagy & Cell Death, Post-translational Modifications, Proteolysis & Proteomics, Systems & Computational Biology Articles Source Type: research
MIWI2 targets RNAs transcribed from piRNA-dependent regions to drive DNA methylation in mouse prospermatogonia
Argonaute/Piwi proteins can regulate gene expression via RNA degradation and translational regulation using small RNAs as guides. They also promote the establishment of suppressive epigenetic marks on repeat sequences in diverse organisms. In mice, the nuclear Piwi protein MIWI2 and Piwi-interacting RNAs (piRNAs) are required for DNA methylation of retrotransposon sequences and some other sequences. However, its underlying molecular mechanisms remain unclear. Here, we show that piRNA-dependent regions are transcribed at the stage when piRNA-mediated DNA methylation takes place. MIWI2 specifically interacts with RNAs from t...
Source: EMBO Journal - September 14, 2018 Category: Molecular Biology Authors: Watanabe, T., Cui, X., Yuan, Z., Qi, H., Lin, H. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, RNA Biology Articles Source Type: research
MIM through MOM: the awakening of Bax and Bak pores
The mechanism whereby mitochondrial DNA (mtDNA) is released into the cytosol and activates the cGAS/STING inflammatory pathway during Bax/Bax-mediated apoptosis is unknown. In this issue, Riley et al (2018) report that widening of Bax and Bak pores on the mitochondrial outer membrane (MOM) during apoptosis allows the extrusion of the mitochondrial inner membrane (MIM) into the cytosol and its permeabilization to release mtDNA independently of caspases. In this scenario, Bax and Bak emerge as key modulators of the apoptotic immunogenic response. (Source: EMBO Journal)
Source: EMBO Journal - September 3, 2018 Category: Molecular Biology Authors: Cosentino, K., Garcia-Saez, A. J. Tags: Autophagy & Cell Death, Membrane & Intracellular Transport, Signal Transduction News [amp ] Views Source Type: research
Hip to the Game: YAP/TAZ is required for nonmelanoma skin cancers
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the two most common skin cancers found in humans. These cancers can acquire drug resistance and pose considerable medical burdens to clinics and patients if left untreated. Two recent studies show that active Hippo signaling plays a critical role in initiating BCC and SCC tumorigenesis, providing new opportunities to develop therapies against these skin malignancies. (Source: EMBO Journal)
Source: EMBO Journal - September 3, 2018 Category: Molecular Biology Authors: Miranda, M. M., Lowry, W. E. Tags: Cancer, Signal Transduction News [amp ] Views Source Type: research
