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Molecular Cell

R Alexander Wesselhoeft, Piotr S Kowalski, Frances C Parker-Hale, Yuxuan Huang, Namita Bisaria, Daniel G Anderson
Circular RNAs (circRNAs) are a class of single-stranded RNAs with a contiguous structure that have enhanced stability and a lack of end motifs necessary for interaction with various cellular proteins. Here, we show that unmodified exogenous circRNA is able to bypass cellular RNA sensors and thereby avoid provoking an immune response in RIG-I and Toll-like receptor (TLR) competent cells and in mice. The immunogenicity and protein expression stability of circRNA preparations are found to be dependent on purity, with small amounts of contaminating linear RNA leading to robust cellular immune responses...
March 19, 2019: Molecular Cell
Christopher M Kirkham, James N F Scott, Xiaoling Wang, Alastair L Smith, Adam P Kupinski, Anthony M Ford, David R Westhead, Peter G Stockley, Roman Tuma, Joan Boyes
V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo...
March 18, 2019: Molecular Cell
Timothy R Baffi, An-Angela N Van, Wei Zhao, Gordon B Mills, Alexandra C Newton
Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Here, we report that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited...
March 18, 2019: Molecular Cell
Pia-Amata Leimbacher, Samuel E Jones, Ann-Marie K Shorrocks, Mara de Marco Zompit, Matthew Day, Jordy Blaauwendraad, Diana Bundschuh, Sarah Bonham, Roman Fischer, Daniel Fink, Benedikt M Kessler, Antony W Oliver, Laurence H Pearl, Andrew N Blackford, Manuel Stucki
In mitosis, cells inactivate DNA double-strand break (DSB) repair pathways to preserve genome stability. However, some early signaling events still occur, such as recruitment of the scaffold protein MDC1 to phosphorylated histone H2AX at DSBs. Yet, it remains unclear whether these events are important for maintaining genome stability during mitosis. Here, we identify a highly conserved protein-interaction surface in MDC1 that is phosphorylated by CK2 and recognized by the DNA-damage response mediator protein TOPBP1...
March 18, 2019: Molecular Cell
Unmesh Jadhav, Alessia Cavazza, Kushal K Banerjee, Huafeng Xie, Nicholas K O'Neill, Veronica Saenz-Vash, Zachary Herbert, Shariq Madha, Stuart H Orkin, Huili Zhai, Ramesh A Shivdasani
Developing and adult tissues use different cis-regulatory elements. Although DNA at some decommissioned embryonic enhancers is hypomethylated in adult cells, it is unknown whether this putative epigenetic memory is complete and recoverable. We find that, in adult mouse cells, hypomethylated CpG dinucleotides preserve a nearly complete archive of tissue-specific developmental enhancers. Sites that carry the active histone mark H3K4me1, and are therefore considered "primed," are mainly cis elements that act late in organogenesis...
March 15, 2019: Molecular Cell
Miho Shimada, Wei-Yi Chen, Tomoyoshi Nakadai, Takashi Onikubo, Mohamed Guermah, Daniela Rhodes, Robert G Roeder
Linker histone H1 has been correlated with transcriptional inhibition, but the mechanistic basis of the inhibition and its reversal during gene activation has remained enigmatic. We report that H1-compacted chromatin, reconstituted in vitro, blocks transcription by abrogating core histone modifications by p300 but not activator and p300 binding. Transcription from H1-bound chromatin is elicited by the H1 chaperone NAP1, which is recruited in a gene-specific manner through direct interactions with activator-bound p300 that facilitate core histone acetylation (by p300) and concomitant eviction of H1 and H2A-H2B...
March 15, 2019: Molecular Cell
Shanming Ji, Yuewan Luo, Qingshuang Cai, Zhijie Cao, Yuanyuan Zhao, Jie Mei, Chenxiao Li, Pengyan Xia, Zhongwen Xie, Zongping Xia, Jian Zhang, Qinmiao Sun, Dahua Chen
In eukaryotic cells, RNA-binding proteins (RBPs) interact with RNAs to form ribonucleoprotein complexes (RNA granules) that have long been thought to regulate RNA fate or activity. Emerging evidence suggests that some RBPs not only bind RNA but also possess enzymatic activity related to ubiquitin regulation, raising important questions of whether these RBP-formed RNA granules regulate ubiquitin signaling and related biological functions. Here, we show that Drosophila Otu binds RNAs and coalesces to membrane-less biomolecular condensates via its intrinsically disordered low-complexity domain, and coalescence represents a functional state for Otu exerting deubiquitinase activity...
March 11, 2019: Molecular Cell
Xiaohan Ning, Yutao Wang, Miao Jing, Mengyin Sha, Mengze Lv, Pengfei Gao, Rui Zhang, Xiaojun Huang, Ji-Ming Feng, Zhengfan Jiang
Viral infection triggers host defenses through pattern-recognition receptor-mediated cytokine production, inflammasome activation, and apoptosis of the infected cells. Inflammasome-activated caspases are known to cleave cyclic GMP-AMP synthase (cGAS). Here, we found that apoptotic caspases are critically involved in regulating both DNA and RNA virus-triggered host defenses, in which activated caspase-3 cleaved cGAS, MAVS, and IRF3 to prevent cytokine overproduction. Caspase-3 was exclusively required in human cells, whereas caspase-7 was involved only in murine cells to inactivate cGAS, reflecting distinct regulatory mechanisms in different species...
March 11, 2019: Molecular Cell
Henriette Aksnes, Rasmus Ree, Thomas Arnesen
Recent studies of N-terminal acetylation have identified new N-terminal acetyltransferases (NATs) and expanded the known functions of these enzymes beyond their roles as ribosome-associated co-translational modifiers. For instance, the identification of Golgi- and chloroplast-associated NATs shows that acetylation of N termini also happens post-translationally. In addition, we now appreciate that some NATs are highly specific; for example, a dedicated NAT responsible for post-translational N-terminal acetylation of actin was recently revealed...
March 11, 2019: Molecular Cell
Rana Elkholi, Ioana Abraham-Enachescu, Andrew P Trotta, Camila Rubio-Patiño, Jarvier N Mohammed, Mark P A Luna-Vargas, Jesse D Gelles, Joshua R Kaminetsky, Madhavika N Serasinghe, Cindy Zou, Sumaira Ali, Gavin P McStay, Cathie M Pfleger, Jerry Edward Chipuk
Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis...
March 9, 2019: Molecular Cell
Sezen Meydan, James Marks, Dorota Klepacki, Virag Sharma, Pavel V Baranov, Andrew E Firth, Tōnu Margus, Amira Kefi, Nora Vázquez-Laslop, Alexander S Mankin
The use of alternative translation initiation sites enables production of more than one protein from a single gene, thereby expanding the cellular proteome. Although several such examples have been serendipitously found in bacteria, genome-wide mapping of alternative translation start sites has been unattainable. We found that the antibiotic retapamulin specifically arrests initiating ribosomes at start codons of the genes. Retapamulin-enhanced Ribo-seq analysis (Ribo-RET) not only allowed mapping of conventional initiation sites at the beginning of the genes, but strikingly, it also revealed putative internal start sites in a number of Escherichia coli genes...
March 8, 2019: Molecular Cell
Florian H Schopf, Eva M Huber, Christopher Dodt, Abraham Lopez, Maximilian M Biebl, Daniel A Rutz, Moritz Mühlhofer, Gesa Richter, Tobias Madl, Michael Sattler, Michael Groll, Johannes Buchner
The Hsp90 chaperone machinery in eukaryotes comprises a number of distinct accessory factors. Cns1 is one of the few essential co-chaperones in yeast, but its structure and function remained unknown. Here, we report the X-ray structure of the Cns1 fold and NMR studies on the partly disordered, essential segment of the protein. We demonstrate that Cns1 is important for maintaining translation elongation, specifically chaperoning the elongation factor eEF2. In this context, Cns1 interacts with the novel co-factor Hgh1 and forms a quaternary complex together with eEF2 and Hsp90...
March 8, 2019: Molecular Cell
Leonie Mönkemeyer, Courtney L Klaips, David Balchin, Roman Körner, F Ulrich Hartl, Andreas Bracher
Eukaryotic elongation factor 2 (eEF2) is an abundant and essential component of the translation machinery. The biogenesis of this 93 kDa multi-domain protein is assisted by the chaperonin TRiC/CCT. Here, we show in yeast cells that the highly conserved protein Hgh1 (FAM203 in humans) is a chaperone that cooperates with TRiC in eEF2 folding. In the absence of Hgh1, a substantial fraction of newly synthesized eEF2 is degraded or aggregates. We solved the crystal structure of Hgh1 and analyzed the interaction of wild-type and mutant Hgh1 with eEF2...
March 6, 2019: Molecular Cell
Jose Norberto S Vargas, Chunxin Wang, Eric Bunker, Ling Hao, Dragan Maric, Giampietro Schiavo, Felix Randow, Richard J Youle
Selective autophagy recycles damaged organelles and clears intracellular pathogens to prevent their aberrant accumulation. How ULK1 kinase is targeted and activated during selective autophagic events remains to be elucidated. In this study, we used chemically inducible dimerization (CID) assays in tandem with CRISPR KO lines to systematically analyze the molecular basis of selective autophagosome biogenesis. We demonstrate that ectopic placement of NDP52 on mitochondria or peroxisomes is sufficient to initiate selective autophagy by focally localizing and activating the ULK1 complex...
March 6, 2019: Molecular Cell
Lea Duempelmann, Fabio Mohn, Yukiko Shimada, Daniele Oberti, Aude Andriollo, Silke Lochs, Marc Bühler
Small RNAs trigger the formation of epialleles that are silenced across generations. Consequently, RNA-directed epimutagenesis is associated with persistent gene repression. Here, we demonstrate that small interfering RNA-induced epimutations in fission yeast are still inherited even when the silenced gene is reactivated, and descendants can reinstate the silencing phenotype that only occurred in their ancestors. This process is mediated by the deposition of a phenotypically neutral molecular mark composed of tri-methylated histone H3 lysine 9 (H3K9me3)...
March 5, 2019: Molecular Cell
Jamie Richards, Joel G Belasco
The diversity of mRNA lifetimes in bacterial cells is difficult to reconcile with the relaxed cleavage site specificity of RNase E, the endonuclease most important for governing mRNA degradation. This enzyme has generally been thought to locate cleavage sites by searching freely in three dimensions. However, our results now show that its access to such sites in 5'-monophosphorylated RNA is hindered by obstacles-such as bound proteins or ribosomes or coaxial small RNA (sRNA) base pairing-that disrupt the path from the 5' end to those sites and prolong mRNA lifetimes...
March 4, 2019: Molecular Cell
MaryClare F Rollins, Saikat Chowdhury, Joshua Carter, Sarah M Golden, Heini M Miettinen, Andrew Santiago-Frangos, Dominick Faith, C Martin Lawrence, Gabriel C Lander, Blake Wiedenheft
Bacteria and archaea have evolved sophisticated adaptive immune systems that rely on CRISPR RNA (crRNA)-guided detection and nuclease-mediated elimination of invading nucleic acids. Here, we present the cryo-electron microscopy (cryo-EM) structure of the type I-F crRNA-guided surveillance complex (Csy complex) from Pseudomonas aeruginosa bound to a double-stranded DNA target. Comparison of this structure to previously determined structures of this complex reveals a ∼180-degree rotation of the C-terminal helical bundle on the "large" Cas8f subunit...
March 1, 2019: Molecular Cell
Tom D Deegan, Jonathan Baxter, María Ángeles Ortiz Bazán, Joseph T P Yeeles, Karim P M Labib
The convergence of two DNA replication forks creates unique problems during DNA replication termination. In E. coli and SV40, the release of torsional strain by type II topoisomerases is critical for converging replisomes to complete DNA synthesis, but the pathways that mediate fork convergence in eukaryotes are unknown. We studied the convergence of reconstituted yeast replication forks that include all core replisome components and both type I and type II topoisomerases. We found that most converging forks stall at a very late stage, indicating a role for additional factors...
March 1, 2019: Molecular Cell
Benjamin J Ravenhill, Keith B Boyle, Natalia von Muhlinen, Cara J Ellison, Glenn R Masson, Elsje G Otten, Agnes Foeglein, Roger Williams, Felix Randow
Xenophagy, a selective autophagy pathway that protects the cytosol against bacterial invasion, relies on cargo receptors that juxtapose bacteria and phagophore membranes. Whether phagophores are recruited from a constitutive pool or are generated de novo at prospective cargo remains unknown. Phagophore formation in situ would require recruitment of the upstream autophagy machinery to prospective cargo. Here, we show that, essential for anti-bacterial autophagy, the cargo receptor NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1, which are subunits of the autophagy-initiating ULK and the TBK1 kinase complex, respectively...
February 28, 2019: Molecular Cell
Yalan Zhu, Ang Gao, Qi Zhan, Yong Wang, Han Feng, Songqing Liu, Guangxia Gao, Alexander Serganov, Pu Gao
Anti-CRISPR proteins (Acrs) targeting CRISPR-Cas9 systems represent natural "off switches" for Cas9-based applications. Recently, AcrIIC1, AcrIIC2, and AcrIIC3 proteins were found to inhibit Neisseria meningitidis Cas9 (NmeCas9) activity in bacterial and human cells. Here we report biochemical and structural data that suggest molecular mechanisms of AcrIIC2- and AcrIIC3-mediated Cas9 inhibition. AcrIIC2 dimer interacts with the bridge helix of Cas9, interferes with RNA binding, and prevents DNA loading into Cas9...
February 28, 2019: Molecular Cell
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