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Molecular Cell

Stefan Grüner, Daniel Peter, Ramona Weber, Lara Wohlbold, Min-Yi Chung, Oliver Weichenrieder, Eugene Valkov, Cátia Igreja, Elisa Izaurralde
Eukaryotic initiation factor 4G (eIF4G) plays a central role in translation initiation through its interactions with the cap-binding protein eIF4E. This interaction is a major drug target for repressing translation and is naturally regulated by 4E-binding proteins (4E-BPs). 4E-BPs and eIF4G compete for binding to the eIF4E dorsal surface via a shared canonical 4E-binding motif, but also contain auxiliary eIF4E-binding sequences, which were assumed to contact non-overlapping eIF4E surfaces. However, it is unknown how metazoan eIF4G auxiliary sequences bind eIF4E...
October 19, 2016: Molecular Cell
Natalia Petrenko, Yi Jin, Koon Ho Wong, Kevin Struhl
Mediator is a transcriptional co-activator recruited to enhancers by DNA-binding activators, and it also interacts with RNA polymerase (Pol) II as part of the preinitiation complex (PIC). We demonstrate that a single Mediator complex associates with the enhancer and core promoter in vivo, indicating that it can physically bridge these transcriptional elements. However, the Mediator kinase module associates strongly with the enhancer, but not with the core promoter, and it dissociates from the enhancer upon depletion of the TFIIH kinase...
October 19, 2016: Molecular Cell
Mahmoud-Reza Rafiee, Charles Girardot, Gianluca Sigismondo, Jeroen Krijgsveld
Maintenance of pluripotency is regulated by a network of transcription factors coordinated by Oct4, Sox2, and Nanog (OSN), yet a systematic investigation of the composition and dynamics of the OSN protein network specifically on chromatin is still missing. Here we have developed a method combining ChIP with selective isolation of chromatin-associated proteins (SICAP) followed by mass spectrometry to identify chromatin-bound partners of a protein of interest. ChIP-SICAP in mouse embryonic stem cells (ESCs) identified over 400 proteins associating with OSN, including several whose interaction depends on the pluripotent state...
October 19, 2016: Molecular Cell
Célia Jeronimo, Marie-France Langelier, Alain R Bataille, John M Pascal, B Franklin Pugh, François Robert
Mediator is a highly conserved transcriptional coactivator organized into four modules, namely Tail, Middle, Head, and Kinase (CKM). Previous work suggests regulatory roles for Tail and CKM, but an integrated model for these activities is lacking. Here, we analyzed the genome-wide distribution of Mediator subunits in wild-type and mutant yeast cells in which RNA polymerase II promoter escape is blocked, allowing detection of transient Mediator forms. We found that although all modules are recruited to upstream activated regions (UAS), assembly of Mediator within the pre-initiation complex is accompanied by the release of CKM...
October 18, 2016: Molecular Cell
Mauricio H Pontes, Jinki Yeom, Eduardo A Groisman
The synthesis of ribosomes is regulated by both amino acid abundance and the availability of ATP, which regenerates guanosine triphosphate (GTP), powers ribosomes, and promotes transcription of rRNA genes. We now report that bacteria supersede both of these controls when experiencing low cytosolic magnesium (Mg(2+)), a divalent cation essential for ribosome stabilization and for neutralization of ATP's negative charge. We uncover a regulatory circuit that responds to low cytosolic Mg(2+) by promoting expression of proteins that import Mg(2+) and lower ATP amounts...
October 8, 2016: Molecular Cell
Daibiao Xiao, Ming Yue, Hexiu Su, Ping Ren, Jue Jiang, Feng Li, Yufeng Hu, Haining Du, Hudan Liu, Guoliang Qing
MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF(Fbw7) ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1...
October 4, 2016: Molecular Cell
Veenu Tripathi, Katherine M Sixt, Shaojian Gao, Xuan Xu, Jing Huang, Roberto Weigert, Ming Zhou, Ying E Zhang
In advanced stages of cancers, TGF-β promotes tumor progression in conjunction with inputs from receptor tyrosine kinase pathways. However, mechanisms that underpin the signaling cooperation and convert TGF-β from a potent growth inhibitor to a tumor promoter are not fully understood. We report here that TGF-β directly regulates alternative splicing of cancer stem cell marker CD44 through a phosphorylated T179 of SMAD3-mediated interaction with RNA-binding protein PCBP1. We show that TGF-β and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35-positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E...
October 4, 2016: Molecular Cell
John F Dankert, Gergely Rona, Linda Clijsters, Phillip Geter, Jeffrey R Skaar, Keria Bermudez-Hernandez, Elizabeth Sassani, David Fenyö, Beatrix Ueberheide, Robert Schneider, Michele Pagano
SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A...
September 24, 2016: Molecular Cell
Jon McGinn, Luciano A Marraffini
CRISPR-Cas systems defend prokaryotes against viruses and plasmids. Short DNA segments of the invader, known as spacers, are stored in the CRISPR array as immunological memories. New spacers are added invariably to the 5' end of the array; therefore, the first spacer matches the latest foreign threat. Whether this highly polarized order of spacer insertion influences CRISPR-Cas immunity has not been explored. Here we show that a conserved sequence located immediately upstream of the CRISPR array specifies the site of new spacer integration...
September 7, 2016: Molecular Cell
Thomas P Garner, Denis E Reyna, Amit Priyadarshi, Hui-Chen Chen, Sheng Li, Yang Wu, Yogesh Tengarai Ganesan, Vladimir N Malashkevich, Emily H Cheng, Evripidis Gavathiotis
No abstract text is available yet for this article.
October 20, 2016: Molecular Cell
Chongsheng He, Simone Sidoli, Robert Warneford-Thomson, Deirdre C Tatomer, Jeremy E Wilusz, Benjamin A Garcia, Roberto Bonasio
Interactions between noncoding RNAs and chromatin proteins play important roles in gene regulation, but the molecular details of most of these interactions are unknown. Using protein-RNA photocrosslinking and mass spectrometry on embryonic stem cell nuclei, we identified and mapped, at peptide resolution, the RNA-binding regions in ∼800 known and previously unknown RNA-binding proteins, many of which are transcriptional regulators and chromatin modifiers. In addition to known RNA-binding motifs, we detected several protein domains previously unknown to function in RNA recognition, as well as non-annotated and/or disordered regions, suggesting that many functional protein-RNA contacts remain unexplored...
October 20, 2016: Molecular Cell
Advaitha Madireddy, Settapong T Kosiyatrakul, Rebecca A Boisvert, Emilia Herrera-Moyano, María L García-Rubio, Jeannine Gerhardt, Elizabeth A Vuono, Nichole Owen, Zi Yan, Susan Olson, Andrés Aguilera, Niall G Howlett, Carl L Schildkraut
Common fragile sites (CFSs) are genomic regions that are unstable under conditions of replicative stress. Although the characteristics of CFSs that render them vulnerable to stress are associated mainly with replication, the cellular pathways that protect CFSs during replication remain unclear. Here, we identify and describe a role for FANCD2 as a trans-acting facilitator of CFS replication, in the absence of exogenous replicative stress. In the absence of FANCD2, replication forks stall within the AT-rich fragility core of CFS, leading to dormant origin activation...
October 20, 2016: Molecular Cell
Ana Rita Araujo, Lendert Gelens, Rahuman S M Sheriff, Silvia D M Santos
Cell division is characterized by a sequence of events by which a cell gives rise to two daughter cells. Quantitative measurements of cell-cycle dynamics in single cells showed that despite variability in G1-, S-, and G2 phases, duration of mitosis is short and remarkably constant. Surprisingly, there is no correlation between cell-cycle length and mitotic duration, suggesting that mitosis is temporally insulated from variability in earlier cell-cycle phases. By combining live cell imaging and computational modeling, we showed that positive feedback is the molecular mechanism underlying the temporal insulation of mitosis...
October 20, 2016: Molecular Cell
Steven Z Josefowicz, Miho Shimada, Anja Armache, Charles H Li, Rand M Miller, Shu Lin, Aerin Yang, Brian D Dill, Henrik Molina, Hee-Sung Park, Benjamin A Garcia, Jack Taunton, Robert G Roeder, C David Allis
The inflammatory response requires coordinated activation of both transcription factors and chromatin to induce transcription for defense against pathogens and environmental insults. We sought to elucidate the connections between inflammatory signaling pathways and chromatin through genomic footprinting of kinase activity and unbiased identification of prominent histone phosphorylation events. We identified H3 serine 28 phosphorylation (H3S28ph) as the principal stimulation-dependent histone modification and observed its enrichment at induced genes in mouse macrophages stimulated with bacterial lipopolysaccharide...
October 20, 2016: Molecular Cell
Raffaela Torggler, Daniel Papinski, Thorsten Brach, Levent Bas, Martina Schuschnig, Thaddäus Pfaffenwimmer, Sabrina Rohringer, Tamara Matzhold, David Schweida, Andrea Brezovich, Claudine Kraft
Autophagy is a potent cellular degradation pathway, and its activation needs to be tightly controlled. Cargo receptors mediate selectivity during autophagy by bringing cargo to the scaffold protein Atg11 and, in turn, to the autophagic machinery, including the central autophagy kinase Atg1. Here we show how selective autophagy is tightly regulated in space and time to prevent aberrant Atg1 kinase activation and autophagy induction. We established an induced bypass approach (iPass) that combines genetic deletion with chemically induced dimerization to evaluate the roles of Atg13 and cargo receptors in Atg1 kinase activation and selective autophagy progression...
October 20, 2016: Molecular Cell
Zheng Luo, Qin Yang, Li Yang
RNA sequence motifs are not sufficient for association with RBPs. In this issue of Molecular Cell, Taliaferro et al. (2016) demonstrate that, other than sequence motif, RNA secondary structure plays a repressive role on RBP binding, both in vitro and in vivo.
October 20, 2016: Molecular Cell
Sinéad Kinsella, Jochen H M Prehn
In this issue of Molecular Cell, Fu et al. (2016) present a detailed structural analysis of death-inducing signaling complex (DISC) assembly and regulation through flexible caspase-8 interactions with cFLIPL, cFLIPS, and the viral inhibitor MC159, thereby identifying novel apoptosis control mechanisms.
October 20, 2016: Molecular Cell
Ariadne Vlahakis, Jayanta Debnath
In this issue of Molecular Cell, Torggler et al. (2016) leverage innovative synthetic biology approaches to dissect the spatiotemporal activation of Atg1 kinase during selective autophagy, revealing two distinct pathways that coordinately initiate autophagosome formation at the yeast vacuole.
October 20, 2016: Molecular Cell
Fumiaki Ohtake, Yasushi Saeki, Satoshi Ishido, Jun Kanno, Keiji Tanaka
Polyubiquitin chains of different topologies regulate diverse cellular processes. K48- and K63-linked chains, the two most abundant chain types, regulate proteolytic and signaling pathways, respectively. Although recent studies reported important roles for heterogeneous chains, the functions of branched ubiquitin chains remain unclear. Here, we show that the ubiquitin chain branched at K48 and K63 regulates nuclear factor κB (NF-κB) signaling. A mass-spectrometry-based quantification strategy revealed that K48-K63 branched ubiquitin linkages are abundant in cells...
October 20, 2016: Molecular Cell
Julyun Oh, Amr Al-Zain, Elda Cannavo, Petr Cejka, Lorraine S Symington
The Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex orchestrates the cellular response to DSBs through its structural, enzymatic, and signaling roles. Xrs2/Nbs1 is essential for nuclear translocation of Mre11, but its role as a component of the complex is not well defined. Here, we demonstrate that nuclear localization of Mre11 (Mre11-NLS) is able to bypass several functions of Xrs2, including DNA end resection, meiosis, hairpin resolution, and cellular resistance to clastogens. Using purified components, we show that the MR complex has equivalent activity to MRX in cleavage of protein-blocked DNA ends...
October 20, 2016: Molecular Cell
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