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Molecular Cell

Karen Yap, Svetlana Mukhina, Gen Zhang, Jason S C Tan, Hong Sheng Ong, Eugene V Makeyev
Functions of many long noncoding RNAs (lncRNAs) depend on their ability to interact with multiple copies of specific RNA-binding proteins (RBPs). Here, we devised a workflow combining bioinformatics and experimental validation steps to systematically identify RNAs capable of multivalent RBP recruitment. This uncovered a number of previously unknown transcripts encoding high-density RBP recognition arrays within genetically normal short tandem repeats. We show that a top-scoring hit in this screen, lncRNA PNCTR, contains hundreds of pyrimidine tract-binding protein (PTBP1)-specific motifs allowing it to sequester a substantial fraction of PTBP1 in a nuclear body called perinucleolar compartment...
October 6, 2018: Molecular Cell
Orel Mizrahi, Aharon Nachshon, Alina Shitrit, Idit A Gelbart, Martina Dobesova, Shirly Brenner, Chaim Kahana, Noam Stern-Ginossar
mRNAs carry two layers of information, the genetic code and the information that dictates their post-transcriptional fate. The latter function relies on a complex interplay between cis-elements and trans-regulators, and unbiased identification of these elements is still challenging. To identify cis-elements that control gene expression, we use dimethyl sulfate (DMS) mutational profiling with sequencing and map changes in mRNA secondary structure following viral infection. Our dynamic structural data reveal a major role for ribosomes in unwinding secondary structures, which is further supported by the relationship we uncover between structure and translation efficiency...
October 5, 2018: Molecular Cell
Nishita Shastri, Yu-Chen Tsai, Suzanne Hile, Deondre Jordan, Barrett Powell, Jessica Chen, Dillon Maloney, Marei Dose, Yancy Lo, Theonie Anastassiadis, Osvaldo Rivera, Taehyong Kim, Sharvin Shah, Piyush Borole, Kanika Asija, Xiang Wang, Kevin D Smith, Darren Finn, Jonathan Schug, Rafael Casellas, Liliya A Yatsunyk, Kristin A Eckert, Eric J Brown
DNA polymerase stalling activates the ATR checkpoint kinase, which in turn suppresses fork collapse and breakage. Herein, we describe use of ATR inhibition (ATRi) as a means to identify genomic sites of problematic DNA replication in murine and human cells. Over 500 high-resolution ATR-dependent sites were ascertained using two distinct methods: replication protein A (RPA)-chromatin immunoprecipitation (ChIP) and breaks identified by TdT labeling (BrITL). The genomic feature most strongly associated with ATR dependence was repetitive DNA that exhibited high structure-forming potential...
October 4, 2018: Molecular Cell
Szymon Juszkiewicz, Viswanathan Chandrasekaran, Zhewang Lin, Sebastian Kraatz, V Ramakrishnan, Ramanujan S Hegde
Aberrantly slow translation elicits quality control pathways initiated by the ubiquitin ligase ZNF598. How ZNF598 discriminates physiologic from pathologic translation complexes and ubiquitinates stalled ribosomes selectively is unclear. Here, we find that the minimal unit engaged by ZNF598 is the collided di-ribosome, a molecular species that arises when a trailing ribosome encounters a slower leading ribosome. The collided di-ribosome structure reveals an extensive 40S-40S interface in which the ubiquitination targets of ZNF598 reside...
October 1, 2018: Molecular Cell
Gunjan D Mehta, David A Ball, Peter R Eriksson, Razvan V Chereji, David J Clark, James G McNally, Tatiana S Karpova
It is unknown how the dynamic binding of transcription factors (TFs) is molecularly linked to chromatin remodeling and transcription. Using single-molecule tracking (SMT), we show that the chromatin remodeler RSC speeds up the search process of the TF Ace1p for its response elements (REs) at the CUP1 promoter. We quantified smFISH mRNA data using a gene bursting model and demonstrated that RSC regulates transcription bursts of CUP1 only by modulating TF occupancy but does not affect initiation and elongation rates...
September 27, 2018: Molecular Cell
Zarmik Moqtaderi, Joseph V Geisberg, Kevin Struhl
Alternative polyadenylation generates numerous 3' mRNA isoforms that can vary in biological properties, such as stability and localization. We developed methods to obtain transcriptome-scale structural information and protein binding on individual 3' mRNA isoforms in vivo. Strikingly, near-identical mRNA isoforms can possess dramatically different structures throughout the 3' UTR. Analyses of identical mRNAs in different species or refolded in vitro indicate that structural differences in vivo are often due to trans-acting factors...
September 26, 2018: Molecular Cell
Stephen M Doris, James Chuang, Olga Viktorovskaya, Magdalena Murawska, Dan Spatt, L Stirling Churchman, Fred Winston
Spt6 is a conserved factor that controls transcription and chromatin structure across the genome. Although Spt6 is viewed as an elongation factor, spt6 mutations in Saccharomyces cerevisiae allow elevated levels of transcripts from within coding regions, suggesting that Spt6 also controls initiation. To address the requirements for Spt6 in transcription and chromatin structure, we have combined four genome-wide approaches. Our results demonstrate that Spt6 represses transcription initiation at thousands of intragenic promoters...
September 26, 2018: Molecular Cell
Verónica Delgado-Benito, Daniel B Rosen, Qiao Wang, Anna Gazumyan, Joy A Pai, Thiago Y Oliveira, Devakumar Sundaravinayagam, Wenzhu Zhang, Matteo Andreani, Lisa Keller, Kyong-Rim Kieffer-Kwon, Aleksandra Pękowska, Seolkyoung Jung, Madlen Driesner, Roman I Subbotin, Rafael Casellas, Brian T Chait, Michel C Nussenzweig, Michela Di Virgilio
Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3' Igh super-enhancer, 3' regulatory region (3'RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3'RR...
September 26, 2018: Molecular Cell
Hong Wang, Amina Boussouar, Laetitia Mazelin, Servane Tauszig-Delamasure, Yan Sun, David Goldschneider, Andrea Paradisi, Patrick Mehlen
c-Kit is a classic proto-oncogene either mutated or upregulated in cancer cells, and this leads to its constitutive kinase activation and, thus, to uncontrolled proliferation. Although the pro-oncogenic role of c-Kit is of no doubt, some observations do not fit well with c-Kit solely as a tumor-promoting moiety. We show here that c-Kit actively triggers cell death in various cancer cell lines unless engaged by its ligand stem cell factor (SCF). This pro-death activity is enhanced when the kinase activation of c-Kit is silenced and is due to c-Kit intracellular cleavage by caspase-like protease at D816...
September 25, 2018: Molecular Cell
Juanjuan Yuan, Yunqing Ma, Tao Huang, Yanhao Chen, Yuanzheng Peng, Bing Li, Jia Li, Yuchen Zhang, Bing Song, Xiaofang Sun, Qiurong Ding, Yan Song, Xing Chang
RNA splicing is a critical mechanism by which to modify transcriptome, and its dysregulation is the underlying cause of many human diseases. It remains challenging, however, to genetically modulate a splicing event in its native context. Here, we demonstrate that a CRISPR-guided cytidine deaminase (i.e., targeted-AID mediated mutagenesis [TAM]) can efficiently modulate various forms of mRNA splicing. By converting invariant guanines to adenines at either 5' or 3' splice sites (SS), TAM induces exon skipping, activation of alternative SS, switching between mutually exclusive exons, or targeted intron retention...
September 21, 2018: Molecular Cell
Thomas Clouaire, Vincent Rocher, Anahita Lashgari, Coline Arnould, Marion Aguirrebengoa, Anna Biernacka, Magdalena Skrzypczak, François Aymard, Bernard Fongang, Norbert Dojer, Jason S Iacovoni, Maga Rowicka, Krzysztof Ginalski, Jacques Côté, Gaëlle Legube
Double-strand breaks (DSBs) are extremely detrimental DNA lesions that can lead to cancer-driving mutations and translocations. Non-homologous end joining (NHEJ) and homologous recombination (HR) represent the two main repair pathways operating in the context of chromatin to ensure genome stability. Despite extensive efforts, our knowledge of DSB-induced chromatin still remains fragmented. Here, we describe the distribution of 20 chromatin features at multiple DSBs spread throughout the human genome using ChIP-seq...
September 21, 2018: Molecular Cell
Katarzyna J Bandyra, Joanna M Wandzik, Ben F Luisi
The endoribonuclease RNase E is a principal factor in RNA turnover and processing that helps to exercise fine control of gene expression in bacteria. While its catalytic activity can be strongly influenced by the chemical identity of the 5' end of RNA substrates, the enzyme can also cleave numerous substrates irrespective of the chemistry of their 5' ends through a mechanism that has remained largely unexplained. We report structural and functional data illuminating details of both operational modes. Our crystal structure of RNase E in complex with the sRNA RprA reveals a duplex recognition site that saddles an inter-protomer surface to help present substrates for cleavage...
September 20, 2018: Molecular Cell
Han Han, Ruxi Qi, Jeff Jiajing Zhou, Albert Paul Ta, Bing Yang, Hiroki J Nakaoka, Gayoung Seo, Kun-Liang Guan, Ray Luo, Wenqi Wang
The Hippo pathway plays a crucial role in organ size control and tumor suppression, but its precise regulation is not fully understood. In this study, we discovered that phosphatidic acid (PA)-related lipid signaling is a key regulator of the Hippo pathway. Supplementing PA in various Hippo-activating conditions activates YAP. This PA-related lipid signaling is involved in Rho-mediated YAP activation. Mechanistically, PA directly interacts with Hippo components LATS and NF2 to disrupt LATS-MOB1 complex formation and NF2-mediated LATS membrane translocation and activation, respectively...
September 13, 2018: Molecular Cell
Andrés Mansisidor, Temistocles Molinar, Priyanka Srivastava, Demetri D Dartis, Adriana Pino Delgado, Hannah G Blitzblau, Hannah Klein, Andreas Hochwagen
Copy-number changes generate phenotypic variability in health and disease. Whether organisms protect against copy-number changes is largely unknown. Here, we show that Saccharomyces cerevisiae monitors the copy number of its ribosomal DNA (rDNA) and rapidly responds to copy-number loss with the clonal amplification of extrachromosomal rDNA circles (ERCs) from chromosomal repeats. ERC formation is replicative, separable from repeat loss, and reaches a dynamic steady state that responds to the addition of exogenous rDNA copies...
September 13, 2018: Molecular Cell
Huanyu Qiao, H B D Prasada Rao, Yan Yun, Sumit Sandhu, Jared H Fong, Manali Sapre, Michael Nguyen, Addy Tham, Benjamin W Van, Tiffany Y H Chng, Amy Lee, Neil Hunter
Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death can be triggered by defects in chromosome synapsis and recombination, which involve repair of DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocyte elimination in meiotic mutants require RNF212. RNF212 sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse and cells transition into quiescence...
September 12, 2018: Molecular Cell
Hamed Mosaei, Vadim Molodtsov, Bernhard Kepplinger, John Harbottle, Christopher William Moon, Rose Elizabeth Jeeves, Lucia Ceccaroni, Yeonoh Shin, Stephanie Morton-Laing, Emma Claire Louise Marrs, Corinne Wills, William Clegg, Yulia Yuzenkova, John David Perry, Joanna Bacon, Jeff Errington, Nicholas Edward Ellis Allenby, Michael John Hall, Katsuhiko S Murakami, Nikolay Zenkin
Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis)...
September 12, 2018: Molecular Cell
Ling Cai, Yi-Hsuan Tsai, Ping Wang, Jun Wang, Dongxu Li, Huitao Fan, Yilin Zhao, Rohan Bareja, Rui Lu, Elizabeth M Wilson, Andrea Sboner, Young E Whang, Deyou Zheng, Joel S Parker, H Shelton Earp, Gang Greg Wang
Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4...
September 11, 2018: Molecular Cell
Swapnil C Devarkar, Brandon Schweibenz, Chen Wang, Joseph Marcotrigiano, Smita S Patel
RIG-I has a remarkable ability to specifically select viral 5'ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in RNA discrimination and activation, but the underlying mechanism was unclear. Using transient-state kinetics, we elucidated the ATPase-driven "kinetic proofreading" mechanism of RIG-I activation and RNA discrimination, akin to DNA polymerases, ribosomes, and T cell receptors. Even in the autoinhibited state of RIG-I, the C-terminal domain kinetically discriminates against self-RNAs by fast off rates...
September 7, 2018: Molecular Cell
Kazushige Kuroha, Alexandra Zinoviev, Christopher U T Hellen, Tatyana V Pestova
The ribosome-associated quality control (RQC) pathway degrades nascent chains (NCs) arising from interrupted translation. First, recycling factors split stalled ribosomes, yielding NC-tRNA/60S ribosome-nascent chain complexes (60S RNCs). 60S RNCs associate with NEMF, which recruits the E3 ubiquitin ligase Listerin that ubiquitinates NCs. The mechanism of subsequent ribosomal release of Ub-NCs remains obscure. We found that, in non-ubiquitinated 60S RNCs and 80S RNCs formed on non-stop mRNAs, tRNA is not firmly fixed in the P site, which allows peptidyl-tRNA hydrolase Ptrh1 to cleave NC-tRNA, suggesting the existence of a pathway involving release of non-ubiquitinated NCs...
September 5, 2018: Molecular Cell
Shu-Lin Liu, Zhi-Gang Wang, Yusi Hu, Yao Xin, Indira Singaram, Sukhamoy Gorai, Xin Zhou, Yoonjung Shim, Jung-Hyun Min, Liang-Wei Gong, Nissim Hay, Jin Zhang, Wonhwa Cho
Activation of class I phosphatidylinositol 3-kinase (PI3K) leads to formation of phosphatidylinositol-3,4,5-trisphophate (PIP3 ) and phosphatidylinositol-3,4-bisphophate (PI34P2 ), which spatiotemporally coordinate and regulate a myriad of cellular processes. By simultaneous quantitative imaging of PIP3 and PI34P2 in live cells, we here show that they have a distinctively different spatiotemporal distribution and history in response to growth factor stimulation, which allows them to selectively induce the membrane recruitment and activation of Akt isoforms...
August 28, 2018: Molecular Cell
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