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Molecular Cell

Ugo Dionne, François J M Chartier, Yossef López de Los Santos, Noémie Lavoie, David N Bernard, Sara L Banerjee, François Otis, Kévin Jacquet, Michel G Tremblay, Mani Jain, Sylvie Bourassa, Gerald D Gish, Jean-Philippe Gagné, Guy G Poirier, Patrick Laprise, Normand Voyer, Christian R Landry, Nicolas Doucet, Nicolas Bisson
Phosphotyrosine (pTyr) signaling has evolved into a key cell-to-cell communication system. Activated receptor tyrosine kinases (RTKs) initiate several pTyr-dependent signaling networks by creating the docking sites required for the assembly of protein complexes. However, the mechanisms leading to network disassembly and its consequence on signal transduction remain essentially unknown. We show that activated RTKs terminate downstream signaling via the direct phosphorylation of an evolutionarily conserved Tyr present in most SRC homology (SH) 3 domains, which are often part of key hub proteins for RTK-dependent signaling...
June 9, 2018: Molecular Cell
Yoav Voichek, Karin Mittelman, Yulia Gordon, Raz Bar-Ziv, David Lifshitz Smit, Rom Shenhav, Naama Barkai
DNA replication introduces a dosage imbalance between early and late replicating genes. In budding yeast, buffering gene expression against this imbalance depends on marking replicated DNA by H3K56 acetylation (H3K56ac). Whether additional processes are required for suppressing transcription from H3K56ac-labeled DNA remains unknown. Here, using a database-guided candidate screen, we find that COMPASS, the H3K4 methyltransferase, and its upstream effector, PAF1C, act downstream of H3K56ac to buffer expression...
June 5, 2018: Molecular Cell
Itziar Serna Martin, Narin Hengrung, Max Renner, Jane Sharps, Mónica Martínez-Alonso, Simonas Masiulis, Jonathan M Grimes, Ervin Fodor
Influenza virus RNA polymerase (FluPol), a heterotrimer composed of PB1, PB2, and PA subunits (P3 in influenza C), performs both transcription and replication of the viral RNA genome. For transcription, FluPol interacts with the C-terminal domain (CTD) of RNA polymerase II (Pol II), which enables FluPol to snatch capped RNA primers from nascent host RNAs. Here, we describe the co-crystal structure of influenza C virus polymerase (FluPolC ) bound to a Ser5-phosphorylated CTD (pS5 -CTD) peptide. The position of the CTD-binding site at the interface of PB1, P3, and the flexible PB2 C-terminal domains suggests that CTD binding stabilizes the transcription-competent conformation of FluPol...
May 25, 2018: Molecular Cell
Long He, Ana P Gomes, Xin Wang, Sang Oh Yoon, Gina Lee, Michal J Nagiec, Sungyun Cho, Andre Chavez, Tasnia Islam, Yonghao Yu, John M Asara, Bo Yeon Kim, John Blenis
The mammalian Target of Rapamycin Complex 1 (mTORC1)-signaling system plays a critical role in the maintenance of cellular homeostasis by sensing and integrating multiple extracellular and intracellular cues. Therefore, uncovering the effectors of mTORC1 signaling is pivotal to understanding its pathophysiological effects. Here we report that the transcription factor forkhead/winged helix family k1 (Foxk1) is a mediator of mTORC1-regulated gene expression. Surprisingly, Foxk1 phosphorylation is increased upon mTORC1 suppression, which elicits a 14-3-3 interaction, a reduction of DNA binding, and nuclear exclusion...
May 24, 2018: Molecular Cell
Eva K Brinkman, Tao Chen, Marcel de Haas, Hanna A Holland, Waseem Akhtar, Bas van Steensel
The RNA-guided DNA endonuclease Cas9 is a powerful tool for genome editing. Little is known about the kinetics and fidelity of the double-strand break (DSB) repair process that follows a Cas9 cutting event in living cells. Here, we developed a strategy to measure the kinetics of DSB repair for single loci in human cells. Quantitative modeling of repaired DNA in time series after Cas9 activation reveals variable and often slow repair rates, with half-life times up to ∼10 hr. Furthermore, repair of the DSBs tends to be error prone...
May 24, 2018: Molecular Cell
Vittorio Sartorelli, Pier Lorenzo Puri
Since its discovery as a skeletal muscle-specific transcription factor able to reprogram somatic cells into differentiated myofibers, MyoD has provided an instructive model to understand how transcription factors regulate gene expression. Reciprocally, studies of other transcriptional regulators have provided testable hypotheses to further understand how MyoD activates transcription. Using MyoD as a reference, in this review, we discuss the similarities and differences in the regulatory mechanisms employed by tissue-specific transcription factors to access DNA and regulate gene expression by cooperatively shaping the chromatin landscape within the context of cellular differentiation...
May 19, 2018: Molecular Cell
Shilpa S Dhar, Dongyu Zhao, Tao Lin, Bingnan Gu, Khusboo Pal, Sarah J Wu, Hunain Alam, Jie Lv, Kyuson Yun, Vidya Gopalakrishnan, Elsa R Flores, Paul A Northcott, Veena Rajaram, Wei Li, Ali Shilatifard, Roy V Sillitoe, Kaifu Chen, Min Gyu Lee
Super-enhancers are large clusters of enhancers that activate gene expression. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines active tumor suppressor genes. However, how these epigenomic signatures are regulated for tumor suppression is little understood. Here we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (a COMPASS-like enzyme, also known as KMT2D) in mice spontaneously induces medulloblastoma. Mll4 loss upregulates oncogenic Ras and Notch pathways while downregulating neuronal gene expression programs...
May 18, 2018: Molecular Cell
Tamas Szoradi, Katharina Schaeff, Enrique M Garcia-Rivera, Daniel N Itzhak, Rolf M Schmidt, Peter W Bircham, Kevin Leiss, Juan Diaz-Miyar, Vivian K Chen, Dale Muzzey, Georg H H Borner, Sebastian Schuck
When faced with proteotoxic stress, cells mount adaptive responses to eliminate aberrant proteins. Adaptive responses increase the expression of protein folding and degradation factors to enhance the cellular quality control machinery. However, it is unclear whether and how this augmented machinery acquires new activities during stress. Here, we uncover a regulatory cascade in budding yeast that consists of the hydrophilin protein Roq1/Yjl144w, the HtrA-type protease Ynm3/Nma111, and the ubiquitin ligase Ubr1...
May 18, 2018: Molecular Cell
Peter H Culviner, Michael T Laub
Toxin-antitoxin systems are widely distributed genetic modules that regulate growth and persistence in bacteria. Many systems, including E. coli MazEF, include toxins that are endoribonucleases, but the full set of targets for these toxins remains poorly defined. Previous studies on a limited set of transcripts suggested that MazF creates a pool of leaderless mRNAs that are preferentially translated by specialized ribosomes created through MazF cleavage of mature 16S rRNA. Here, using paired-end RNA sequencing (RNA-seq) and ribosome profiling, we provide a comprehensive, global analysis of MazF cleavage specificity and its targets...
May 17, 2018: Molecular Cell
Ankit Turakhiya, Susanne R Meyer, Gabriella Marincola, Stefanie Böhm, Jens T Vanselow, Andreas Schlosser, Kay Hofmann, Alexander Buchberger
Stress granules (SGs) are cytoplasmic assemblies of mRNPs stalled in translation initiation. They are induced by various stress conditions, including exposure to the environmental toxin and carcinogen arsenic. While perturbed SG turnover is linked to the pathogenesis of neurodegenerative diseases, the molecular mechanisms underlying SG formation and turnover are still poorly understood. Here, we show that ZFAND1 is an evolutionarily conserved regulator of SG clearance. ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs...
May 17, 2018: Molecular Cell
Erik Holmqvist, Lei Li, Thorsten Bischler, Lars Barquist, Jörg Vogel
The conserved RNA-binding protein ProQ has emerged as the centerpiece of a previously unknown third large network of post-transcriptional control in enterobacteria. Here, we have used in vivo UV crosslinking and RNA sequencing (CLIP-seq) to map hundreds of ProQ binding sites in Salmonella enterica and Escherichia coli. Our analysis of these binding sites, many of which are conserved, suggests that ProQ recognizes its cellular targets through RNA structural motifs found in small RNAs (sRNAs) and at the 3' end of mRNAs...
May 15, 2018: Molecular Cell
Roberto Bellelli, Valerie Borel, Clare Logan, Jennifer Svendsen, Danielle E Cox, Emma Nye, Kay Metcalfe, Susan M O'Connell, Gordon Stamp, Helen R Flynn, Ambrosius P Snijders, François Lassailly, Andrew Jackson, Simon J Boulton
DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1...
May 3, 2018: Molecular Cell
Claudia Ribeiro de Almeida, Somdutta Dhir, Ashish Dhir, Amin E Moghaddam, Quentin Sattentau, Anton Meinhart, Nicholas J Proudfoot
Class switch recombination (CSR) at the immunoglobulin heavy-chain (IgH) locus is associated with the formation of R-loop structures over switch (S) regions. While these often occur co-transcriptionally between nascent RNA and template DNA, we now show that they also form as part of a post-transcriptional mechanism targeting AID to IgH S-regions. This depends on the RNA helicase DDX1 that is also required for CSR in vivo. DDX1 binds to G-quadruplex (G4) structures present in intronic switch transcripts and converts them into S-region R-loops...
April 30, 2018: Molecular Cell
Deirdre H McLachlan, Ashley J Pridgeon, Alistair M Hetherington
Takahashi et al. (2018) report that the peptide CLE25 together with the BAM1, BAM3 LRR receptor-like kinases are involved in root-to-shoot communication during dehydration stress in Arabidopsis.
June 21, 2018: Molecular Cell
Richard G Gardner, Tommer Ravid
In the current issue of Molecular Cell, Szoradi et al. (2018) present compelling data demonstrating how the newly identified SHRED pathway in yeast selectively shifts the E3 ligase Ubr1 specificity from N-end rule substrates to misfolded proteins in cells under proteostatic stress.
June 21, 2018: Molecular Cell
Stefan Bresson, David Tollervey
In this issue of Molecular Cell, Webster et al. (2018) and Yi et al. (2018) dissect the mechanisms underlying cytoplasmic mRNA deadenylation by the Ccr4-Not (CNOT) complex. Crucial to this process is the poly(A) binding protein Pab1/PABPC1, which both stimulates and suppresses the activity of different deadenylases.
June 21, 2018: Molecular Cell
Yifan Liu, Yali Dou
Buffering dosage imbalance of early- and late-replicating genes is important for dividing eukaryotic cells. Voichek et al. (2018) described critical roles of H3K4 methylation and Paf1C in this process, which was regulated by the S phase checkpoint and H3K56 acetylation.
June 21, 2018: Molecular Cell
Tiago Baptista, Sebastian Grünberg, Nadège Minoungou, Maria J E Koster, H T Marc Timmers, Steve Hahn, Didier Devys, László Tora
No abstract text is available yet for this article.
June 21, 2018: Molecular Cell
Ozgur Oksuz, Varun Narendra, Chul-Hwan Lee, Nicolas Descostes, Gary LeRoy, Ramya Raviram, Lili Blumenberg, Kelly Karch, Pedro P Rocha, Benjamin A Garcia, Jane A Skok, Danny Reinberg
Polycomb repressive complex 2 (PRC2) maintains gene silencing by catalyzing methylation of histone H3 at lysine 27 (H3K27me2/3) within chromatin. By designing a system whereby PRC2-mediated repressive domains were collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of H3K27me2/3 domain formation became evident. First, PRC2 is stably recruited by the actions of JARID2 and MTF2 to a limited number of spatially interacting "nucleation sites," creating H3K27me3-forming Polycomb foci within the nucleus...
June 21, 2018: Molecular Cell
Naomi J Petela, Thomas G Gligoris, Jean Metson, Byung-Gil Lee, Menelaos Voulgaris, Bin Hu, Sotaro Kikuchi, Christophe Chapard, Wentao Chen, Eeson Rajendra, Madhusudhan Srinivisan, Hongtao Yu, Jan Löwe, Kim A Nasmyth
Cohesin organizes DNA into chromatids, regulates enhancer-promoter interactions, and confers sister chromatid cohesion. Its association with chromosomes is regulated by hook-shaped HEAT repeat proteins that bind Scc1, namely Scc3, Pds5, and Scc2. Unlike Pds5, Scc2 is not a stable cohesin constituent but, as shown here, transiently replaces Pds5. Scc1 mutations that compromise its interaction with Scc2 adversely affect cohesin's ATPase activity and loading. Moreover, Scc2 mutations that alter how the ATPase responds to DNA abolish loading despite cohesin's initial association with loading sites...
June 21, 2018: Molecular Cell
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