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  • Structure of a transcribing RNA polymerase II-U1 snRNP complex
    bioRxiv. Mol. Biol. Pub Date : 2020-10-20
    Suyang Zhang; Shintaro Aibara; Seychelle M Vos; Dmitry E Agafonov; Reinhard Lührmann; Patrick Cramer

    To initiate co-transcriptional splicing, RNA polymerase II (Pol II) recruits U1 small nuclear ribonucleoprotein particle (U1 snRNP) to nascent pre-mRNA. Here we report the cryo-EM structure of a mammalian transcribing Pol II-U1 snRNP complex. The structure reveals that Pol II and U1 snRNP interact directly. This interaction positions the 5' splice site in pre-mRNA near the RNA exit site of Pol II.

    更新日期:2020-10-20
  • Comprehensive deletion landscape of CRISPR-Cas9 identifies minimal RNA-guided DNA-binding modules
    bioRxiv. Mol. Biol. Pub Date : 2020-10-19
    Arik Shams; Sean A Higgins; Christof Fellmann; Thomas J Laughlin; Benjamin L Oakes; Rachel Lew; Maria Lukarska; Madeline Arnold; Brett Staahl; Jennifer A Doudna; David Savage

    Proteins evolve through the modular rearrangement of elements known as domains. It is hypothesized that extant, multidomain proteins are the result of domain accretion, but there has been limited experimental validation of this idea. Here, we introduce a technique for genetic minimization by iterative size-exclusion and recombination (MISER) that comprehensively assays all possible deletions of a protein

    更新日期:2020-10-20
  • Lentiviral vectors transduce lung stem cells without disrupting plasticity
    bioRxiv. Mol. Biol. Pub Date : 2020-10-19
    Ashley L. Cooney; Andrew L. Thurman; Paul B McCray; Alejandro A Pezzulo; Patrick L. Sinn

    Life-long expression of a gene therapy agent likely requires targeting stem cells. Here we ask the question: does viral vector transduction or ectopic expression of a therapeutic transgene preclude airway stem cell function? We used a lentiviral vector containing a GFP or cystic fibrosis transmembrane conductance regulator (CFTR) transgene to transduce primary airway basal cells from human cystic fibrosis

    更新日期:2020-10-20
  • Defective Repression of OLE3::LUC 1 (DROL1) is specifically required for the splicing of AT-AC-type introns in Arabidopsis
    bioRxiv. Mol. Biol. Pub Date : 2020-10-19
    Takamasa Suzuki; Tomomi Shinagawa; Tomoko Niwa; Hibiki Akeda; Satoki Hashimoto; Hideki Tanaka; Fumiya Yamasaki; Tsutae Kawai; Tetsuya Higashiyama; Kenzo Nakamura

    An Arabidopsis mutant named defective repression of OLE3::LUC 1 (drol1) was originally isolated as a mutant with defects in the repression of OLEOSIN3 (OLE3) after seed germination. In this study, we show that DROL1 is an Arabidopsis homolog of yeast DIB1, a subunit of U5 snRNP in the spliceosome, but comprises a subfamily specific to a certain class of eukaryotes. Comprehensive analysis of intron

    更新日期:2020-10-20
  • Role of Mcpip1 in obesity-induced hepatic steatosis as determined by myeloid and liver-specific conditional knockouts.
    bioRxiv. Mol. Biol. Pub Date : 2020-10-19
    Natalia Pydyn; Dariusz Zurawek; Joanna Koziel; Edyta Kus; Kamila Wojnar-Lason; Agnieszka Jasztal; Mingui Fu; Jolanta Jura; Jerzy Kotlinowski

    Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NFκB activity. Moreover, it was demonstrated, that MCPIP1 regulates lipid metabolism both in adipose tissue and hepatocytes. In this study, we investigated the effects of tissue-specific

    更新日期:2020-10-19
  • Subcellular relocalization and nuclear redistribution of the RNA methyltransferases TRMT1 and TRMT1L upon neuronal activation
    bioRxiv. Mol. Biol. Pub Date : 2020-10-17
    Nicky Jonkhout; Sonia Cruciani; Helaine Graziele Santos Vieira; Julia Tran; Huanle Liu; Ganqiang Liu; Russell Pickford; Dominik Kaczorowski; Gloria R Franco; Franz Vauti; Noelia Camacho; Seyedeh Sedigheh Abedini; Hossein Najmabadi; Lluis Ribas de Pouplana; Daniel Christ; Nicole Schonrock; John S Mattick; Eva Maria Novoa

    RNA modifications are dynamic chemical entities that regulate RNA fate, and an avenue for environmental response in neuronal function. However, which RNA modifications may be playing a role in neuronal plasticity and environmental responses is largely unknown. Here we characterize the biochemical function and cellular dynamics of two human RNA methyltransferases previously associated with neurological

    更新日期:2020-10-19
  • Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19
    bioRxiv. Mol. Biol. Pub Date : 2020-10-16
    Qu Deng; Reyaz ur Rasool; Ronnie M Russell; Ramakrishnan Natesan; Irfan A Asangani

    The COVID-19 pandemic is expected to have an adverse effect on the progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm and associated oncogenic signaling. Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation

    更新日期:2020-10-17
  • Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers
    bioRxiv. Mol. Biol. Pub Date : 2020-10-16
    Edurne Rujas; Iga Kucharska; Yong Zi Tan; Samir Benlekbir; Hong Cui; Tiantian Zhao; Gregory A Wasney; Patrick Budylowski; Furkan Guvenc; Jocelyn C Newton; Taylor Sicard; Anthony Semesi; Krithika Muthuraman; Amy Nouanesengsy; Katherine Prieto; Stephanie A Bueler; Sawsan Youssef; Sindy Liao-Chan; Jacob Glanville; Natasha Christie-Holmes; Samira Mubareka; Scott D Gray-Owen; John L Rubinstein; Bebhinn

    The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), has caused a global pandemic. Antibodies are powerful biotherapeutics to fight viral infections; however, discovery of the most potent and broadly acting clones can be lengthy. Here, we used the human apoferritin protomer as a modular subunit to drive oligomerization of antibody

    更新日期:2020-10-17
  • SPF45/RBM17-dependent, but not U2AF-dependent, splicing in human short introns
    bioRxiv. Mol. Biol. Pub Date : 2020-10-16
    Kazuhiro Fukumura; Rei Yoshimoto; Luca Sperotto; Hyun-Seo Kang; Tetsuro Hirose; Kunio Inoue; Michael Sattler; Akila Mayeda

    Human pre-mRNA introns vary in size from under fifty to over a million nucleotides. We searched for essential factors specifically involved in the splicing of human short introns by screening siRNAs against 154 human nuclear proteins for activity on a model short 56-nucleotide intron-containing HNRNPH1 pre-mRNA. We identified a known alternative splicing regulator SPF45 (RBM17) as a general splicing

    更新日期:2020-10-17
  • DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity
    bioRxiv. Mol. Biol. Pub Date : 2020-10-16
    Qian Du; Grady C Smith; Phuc Loi Luu; James M Ferguson; Nicola J Armstrong; C Elizabeth Caldon; Elyssa Campbell; Shalima S Nair; Elena Zotenko; Cathryn M Gould; Michael Buckley; Dominik Kaczorowski; Kirston Barton; Ira W Deveson; Martin A Smith; Joseph E Powell; Ksenia Skvortsova; Clare Stirzaker; Joanna Achinger-Kawecka; Susan J Clark

    DNA replication timing and three-dimensional (3D) genome organisation are associated with distinct epigenome patterns across large domains during differentiation and cancer progression. However, it is unclear if alternations in the epigenome, in particular cancer-associated DNA hypomethylation, can directly promote higher order genome architectural alterations. Here, we use Hi-C and single cell Repli-Seq

    更新日期:2020-10-17
  • Nrd1p identifies aberrant and natural exosomal target messages during the nuclear mRNA surveillance in Saccharomyces cerevisiae
    bioRxiv. Mol. Biol. Pub Date : 2020-10-16
    Pragyan Singh; Anusha Chaudhuri; Mayukh Banerjea; Neeraja Marathe; Biswadip Das

    In all eukaryotes, selective nuclear degradation of aberrant mRNAs by nuclear exosome and its cofactors TRAMP, and CTEXT contribute to the fidelity of the gene expression pipeline. In the model eukaryote, Saccharomyces cerevisiae, the Nrd1p-Nab3p-Sen1p (NNS) complex, previously known to be involved in the transcription termination and matured 3'-end formation of vast majority of non-coding and several

    更新日期:2020-10-17
  • Islet Gene View - a tool to facilitate islet research
    bioRxiv. Mol. Biol. Pub Date : 2020-10-16
    Olof Asplund; Petter Storm; Vikash Chandra; Emilia Ottosson-Laakso; Gad Hatem; Dina Mansour-Aly; Ulrika Krus; Hazem Ibrahim; Emma Ahlqvist; Tiinamaija Tuomi; Erik Renstrom; Olle Korsgren; Nils Wierup; Claes Wollheim; Isabella Artner; Hindrik Mulder; Ola Hansson; Timo Otonkoski; Leif Groop; Rashmi B Prasad

    Changes in the hormone-producing pancreatic islets are central culprits in type 2 diabetes (T2D) pathogenesis. Characterization of gene expression in islets how it is altered in T2D are therefore vital in understanding islet function and T2D pathogenesis. We leveraged RNA-sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information

    更新日期:2020-10-17
  • Chromosomal replication origins in Candida albicans are genetically defined irrespective of their chromosomal context
    bioRxiv. Mol. Biol. Pub Date : 2020-10-15
    SREYOSHI MITRA

    Initiation of DNA replication occurs at specialized regions along chromosomes called origins. The knowledge of replication origins is imperative to understand regulation of DNA replication. The properties of replication origins in the pathogenic budding yeast Candida albicans remain enigmatic in the absence of the knowledge of authentic chromosomal origins. Earlier, we identified centromere proximal

    更新日期:2020-10-17
  • Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland
    bioRxiv. Mol. Biol. Pub Date : 2020-10-15
    Deepika Watts; Nicole Bechmann; Ana Meneses; Ioanna K. Poutakidou; Denise Kaden; Catleen Conrad; Anja Krueger; Johanna Stein; Ali El-Armouche; Triantafyllos Chavakis; Graeme Eisenhofer; Mirko Peitzsch; Ben Wielockx

    The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signalling on its function remains scarcely understood. Here, we reveal that deficiency of HIF (Hypoxia Inducible Factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression

    更新日期:2020-10-17
  • Cas9-mediated Genome Editing Reveals a Significant Contribution of Calcium Signaling Pathways to Anhydrobiosis in Pv11
    bioRxiv. Mol. Biol. Pub Date : 2020-10-15
    Yugo Miyata; Hiroto Fuse; Shoko Tokumoto; Yusuke Hiki; Ruslan Deviatiiarov; Yuki Yoshida; Takahiro G. Yamada; Richard Cornette; Oleg Gusev; Elena Shagimardanova; Akira Funahashi; Takahiro Kikawada

    Pv11 is an insect cell line established from the midge Polypedilum vanderplanki that exhibits an extreme desiccation tolerance known as anhydrobiosis. Pv11 has also an anhydrobiotic ability which is induced by trehalose treatment. Here we report the successful construction of the genome editing system for Pv11 cells and its application for identifying the signaling pathways in the anhydrobiosis. Using

    更新日期:2020-10-17
  • Identification of subfunctionalized aggregate-remodeling J-domain proteins in plants
    bioRxiv. Mol. Biol. Pub Date : 2020-10-15
    Yogesh Tak; Silviya S. Lal; Shilpa Gopan; Madhumitha Balakrishnan; Amit K. Verma; Sierra J. Cole; Rebecca E. Brown; Rachel E. Hayward; Justin K. Hines; Chandan Sahi

    Hsp70s and J-domain proteins (JDPs) are among the most critical components of the cellular protein quality control machinery, playing crucial roles in preventing and solubilizing cytotoxic protein aggregates. Bacteria, yeast and plants additionally have large, multimeric Hsp100-class disaggregases which, allow the resolubilization of otherwise dead-end aggregates, including amyloids. JDPs interact

    更新日期:2020-10-17
  • SLAP2 adaptor binding disrupts c-CBL autoinhibition to activate ubiquitin ligase function
    bioRxiv. Mol. Biol. Pub Date : 2020-10-15
    Leanne E. Wybenga-Groot; Andrea J. Tench; Craig D. Simpson; Jonathan St. Germain; Brian Raught; Michael F. Moran; C. Jane McGlade

    CBL is a RING type E3 ubiquitin ligase that functions as a negative regulator of tyrosine kinase signaling and loss of CBL E3 function is implicated in several forms of leukemia. The Src-like adaptor proteins (SLAP/SLAP2) bind to CBL and are required for CBL-dependent downregulation of antigen receptor, cytokine receptor, and receptor tyrosine kinase signaling. Despite the established role of SLAP/SLAP2

    更新日期:2020-10-17
  • Foxc1 establishes enhancer accessibility for craniofacial cartilage differentiation
    bioRxiv. Mol. Biol. Pub Date : 2020-10-15
    Pengfei Xu; Haoze V Yu; Kuo-Chang Tseng; Mackenzie Flath; Peter Fabian; Neil Segil; J Gage Crump

    The specification of cartilage requires Sox9, a transcription factor with broad roles for organogenesis outside the skeletal system. How Sox9 gains selective access to cartilage specific cis-regulatory regions during skeletal development had remained unclear. By analyzing chromatin accessibility during the differentiation of neural crest cells into chondrocytes of the zebrafish head, we find that

    更新日期:2020-10-16
  • Rapidemic, a versatile and label-free DNAzyme-based platform for visual nucleic acid detection
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Marijn van den Brink; Sebastian T. Tandar; Tim A. P. van den Akker; Sinisha Jovikj; Violette Defourt; Tom G. B. Langelaar; Tijn O. Delzenne; Kelly van Strien; Amber W. Schonk; Aukje J. A. M. Beers; Eugene Golov; Lucy J. Chong; Güniz Özer Bergman; Joey J. W. D. Meijdam; Marjolein E. Crooijmans; Dennis Claessen; Johannes H. de Winde

    In the last three decades, there have been recurring outbreaks of infectious diseases, brought to light with the recent outbreak of coronavirus disease 2019 (COVID-19). Attempts to effectively contain the spread of infectious diseases have been hampered by the lack of rapidly adaptable, accurate, and accessible point-of-care diagnostic testing. In this study, we present a novel design of a label-free

    更新日期:2020-10-16
  • Genotype identification and diversity analysis in Kiwifruit (Actinidia spp.) using RAPD markers
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Aarti Kamboj; Pushpa Kharb; Agrim Jhilta; RAKSHITA Singh

    Kiwifruit (Actinidia spp.) is a significant plantation crop belonging to family Actinidiaceae, having deciduous, dioecious, and scrambling vines with chromosome number 2n=58. Dioecy in kiwifruit forms the basis for several breeding programs. The present study was carried out for diversity analysis in kiwifruit genotypes using RAPD markers. 7 kiwifruit genotypes (2 males viz. Allision & Tomuri and 5

    更新日期:2020-10-16
  • Trade-offs between sperm viability and immune protein expression in honey bee queens (Apis mellifera)
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Alison McAfee; Abigail Chapman; Jeffery Pettis; Leonard Foster; David R Tarpy

    Queens of many social hymenoptera keep sperm alive within their specialized storage organ, the spermatheca, for years, defying the typical trade-off between lifespan and reproduction. However, whether honey bee queens experience a trade-off between reproduction and immunity is unknown, and the biochemical processes underlying sperm viability are poorly understood. Here, we survey quality metrics and

    更新日期:2020-10-16
  • Augmentation of Antibacterial Activity in Mesenchymal Stromal Cells Through Systems-Level Analysis and CRISPR-mediated Activation of CD14
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Matthew P Hirakawa; Nikki Tjahjono; Yooli K Light; Prem Chintalapudi; Kimberly S Butler; Steven S Branda; Raga Krishnakumar

    Mesenchymal stromal cells (MSCs) have broad-ranging therapeutic capabilities, however MSC use is confounded by cell-to-cell heterogeneity, and source-to-source phenotypic inconsistencies. We utilized a systems-based approach to compare MSCs which displayed different capacity for antibacterial activity. Although MSCs from both sources satisfied traditional MSC-defining criteria, comparative transcriptomics

    更新日期:2020-10-16
  • The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Antonin Tidu; Aurelie Janvier; Laure Schaeffer; Piotr Sosnowski; Lauriane Kuhn; Philippe Hammann; Eric Westhof; Gilbert Eriani; Franck Martin

    SARS-CoV-2 coronavirus is responsible for Covid-19 pandemic. In the early phase of infection, the single-strand positive RNA genome is translated into non-structural proteins (NSP). One of the first proteins produced during viral infection, NSP1, binds to the host ribosome and blocks the mRNA entry channel. This triggers translation inhibition of cellular translation. In spite of the presence of NSP1

    更新日期:2020-10-16
  • Methyltransferase-like 3 modulates severe acute respiratory syndrome coronavirus-2 RNA N6-methyladenosine modification and replication
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Xueyan Zhang; Haojie Hao; Li Ma; Yecheng Zhang; Xiao Hu; Zhen Chen; Di Liu; Jianhui Yuan; Zhangli Hu; Wuxiang Guan

    The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an ongoing global public crisis. Although viral RNA modification has been reported based on the transcriptome architecture, the types and functions of RNA modification are still unknown. In this study, we evaluated the roles of RNA N6-methyladenosine (m6A) modification in SARS-CoV-2. Our

    更新日期:2020-10-16
  • RNA regulates Glycolysis and Embryonic Stem Cell Differentiation via Enolase 1
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Ina Huppertz; Joel I. Perez-Perri; Panagiotis Mantas; Thileepan Sekaran; Thomas Schwarzl; Lyudmila Dimitrova-Paternoga; Janosch Hennig; Pierre A. Neveu; Matthias W. Hentze

    Cells must coordinate their metabolism and fate trajectories (1, 2), but the underlying mechanisms are only beginning to be discovered. To understand why the glycolytic enzyme enolase 1 (ENO1) binds RNA (3-6), we studied this phenomenon in vitro, in human cells, and during mouse embryonic stem cell differentiation. We find specific cellular RNA ligands that inhibit ENO1's enzymatic activity in vitro

    更新日期:2020-10-16
  • Importin α2 association with chromatin: Direct DNA binding via a novel DNA binding domain
    bioRxiv. Mol. Biol. Pub Date : 2020-10-14
    Kazuya Jibiki; Takashi Kodama; Atsushi Suenaga; Yota Kawase; Noriko Shibazaki; Shin Nomoto; Seiya Nagasawa; Misaki Nagashima; Shieri Shimodan; Renan Kikuchi; Mina Okayasu; Ruka Takashita; Rashid Mehmood; Noriko Saitoh; Yoshihiro Yoneda; Ken-ich Akagi; Noriko Yasuhara

    Nuclear transport of proteins is important for facilitating appropriate nuclear functions. The proteins of the importin α family play key roles in nuclear transport as transport receptors for a huge number of nuclear proteins. Additionally, these proteins possess other functions, including chromatin association and gene regulation. However, these non-transport functions of importin α are not yet fully

    更新日期:2020-10-15
  • ELOVL2 is required for robust visual function in zebrafish
    bioRxiv. Mol. Biol. Pub Date : 2020-10-13
    Manish Dasyani; Fangyuan Gao; Qianlan Xu; Donald Van Fossan; Ellis Zhang; Antonio F. M. Pinto; Alan Saghatelian; Dorota Skowronska-Krawczyk; Daniel L. Chao

    Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) play critical roles in membrane stability and cell signaling within the retina. Elovl2, an elongase involved in synthesis of long chain polyunsaturated fatty acids (LC-PUFAs), has recently been implicated in regulating aging in the mammalian retina. In this work, we characterize the expression and function of elovl2 in retina development in embryonic

    更新日期:2020-10-15
  • Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation
    bioRxiv. Mol. Biol. Pub Date : 2020-10-13
    Mathieu Botte; Alexander K.C. Ulrich; Ricardo Adaixo; David Gnutt; Andreas Brockmann; Denis Bucher; Mohamed Chami; Nicolas Bocquet; Ulrich Ebbinghaus-Kintscher; Vera Puetter; Andreas Becker; Ursula Egner; Henning Stahlberg; Michael Hennig; Simon J Holton

    The human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the

    更新日期:2020-10-15
  • The mammalian cholesterol synthesis enzyme squalene monooxygenase is proteasomally truncated to a constitutively active form
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Hudson W Coates; Andrew J Brown

    Squalene monooxygenase (SM) is a rate-limiting enzyme of cholesterol synthesis that is oncogenic in a range of cancer types. SM is subject to feedback regulation via cholesterol-induced degradation, which depends on its lipid-sensing N terminal regulatory domain. Here, we characterize an endogenous truncated form of SM and show that it is cholesterol-resistant, and therefore constitutively active.

    更新日期:2020-10-13
  • Genomic Similarity of Nucleotides in SARS CoronaVirus using K-Means Unsupervised Learning Algorithm
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Jairaj Singh

    The drastic increase in the number of coronaviruses discovered and coronavirus genomes being sequenced have given us a great opportunity to perform genomics and bioinformatics analysis on this family of viruses. Coronaviruses possess the largest genomes (26.4 to 31.7 kb) among all known RNA viruses, with G + C contents varying from 32% to 43%. Phylogenetically, three genera, Alphacoronavirus, Betacoronavirus

    更新日期:2020-10-13
  • Replication intermediate architecture reveals the chronology of DNA damage tolerance pathways at UV-stalled replication forks in human cells
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Yann Benureau; Caroline Pouvelle; Eliana Moreira Tavares; Pauline Dupaigne; Emmanuelle Despras; Eric Le Cam; Patricia Kannouche

    DNA lesions in S phase threaten genome stability. The DNA damage tolerance (DDT) pathways overcome these obstacles and allow completion of DNA synthesis by the use of specialised translesion (TLS) DNA polymerases or through recombination-related processes. However, how these mechanisms coordinate with each other and with bulk replication remain elusive. To address these issues, we monitored the variation

    更新日期:2020-10-13
  • A synthetic lethal interaction with a viral-induced hypomorph of GBF1
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Arti T Navare; Fred D Mast; Jean Paul Olivier; Thierry D Bertomeu; Jasmin Coulombe-Huntington; Maxwell Neal; Mike Tyers; John D Aitchison

    Viruses co-opt host proteins to carry out replication of the virus. Host proteins thus repurposed may become functionally compromised, a situation analogous to a loss-of-function allele, which we term a viral-induced hypomorph. Tumor-specific loss-of-function alleles have successfully been targeted with drugs perturbing proteins encoded by the synthetic lethal partners of these cancer-specific mutations

    更新日期:2020-10-13
  • Nup98-dependent transcriptional memory is established independently of transcription
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Maya Capelson; Pau Pascual-Garcia; Shawn Little

    Cellular ability to mount an enhanced transcriptional response upon repeated exposure to external cues is termed transcriptional memory. This phenomenon can be maintained epigenetically through cell divisions and has been found to depend on a nuclear pore component Nup98. To gain a population dynamics perspective on the mechanism of transcriptional memory, we combined single-molecule RNA FISH with

    更新日期:2020-10-13
  • Opposing functions of the Hda1 complex and histone H2B mono-ubiquitylation in regulating cryptic transcription initiation in Saccharomyces cerevisiae
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Margaret K. Shirra; Rachel A. Kocik; Mitchell A. Ellison; Karen M. Arndt

    Maintenance of chromatin structure under the disruptive force of transcription requires cooperation among numerous chromatin regulatory factors. Histone post-translational modifications can regulate nucleosome stability and influence the disassembly and reassembly of nucleosomes during transcription elongation. The Paf1 transcription elongation complex, Paf1C, is required for several transcription-coupled

    更新日期:2020-10-13
  • A Sequence determinant in 3'UTR of mRNAs for Nuclear Retention by Paraspeckles
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Audrey Jacq; Denis Becquet; Benedicte Boyer; Severine Guillen; Maria-Montserrat Bello-Goutierrez; Marie-Pierre Blanchard; Claude Villard; Maya Belghazi; Manon Torres; Jean-Louis Franc; Anne-Marie Francois-Bellan

    Paraspeckles are nuclear membraneless structures composed of a long non-coding RNA, Nuclear-Enriched-Abundant-Transcript-1 and RNA binding proteins, which associate numerous mRNAs. It is therefore believed that their cellular function is to sequester in the nucleus their associated proteins and/or target mRNAs. However, little is known about the molecular determinant in mRNA targets that allow their

    更新日期:2020-10-12
  • Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Lynn Radamaker; Julian David Baur; Stefanie Huhn; Christian Haupt; Ute Hegenbart; Stefan Schönland; Akanksha Bansal; Matthias Schmidt; Marcus Fändrich

    Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present the first ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005)

    更新日期:2020-10-12
  • Characterisation of the Semliki Forest Virus-host cell interactome reveals the viral capsid protein as an inhibitor of nonsense-mediated mRNA decay
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Lara Contu; Giuseppe Balistreri; Michal Domanski; Anne-Christine Uldry; Oliver Muhlemann

    The positive-sense, single-stranded RNA alphaviruses pose a potential epidemic threat. Understanding the complex interactions between the viral and the host cell proteins is crucial for elucidating the mechanisms underlying successful virus replication strategies and for developing specific antiviral interventions. Here we present the first comprehensive protein-protein interaction map between the

    更新日期:2020-10-12
  • Direct measurements of mRNA translation kinetics in living cells
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Mikhail Metelev; Ivan L. Volkov; Erik Lundin; Arvid H. Gynnå Johan Elf; Magnus Johansson

    Ribosome mediated mRNA translation is central to life as we know it. The cycle of translation has, however, not been characterized in a living cell. Here we have developed a live-cell ribosome-labeling method, which allows us to characterize the whole processes of finding an mRNA and translating it, using single-molecule tracking techniques. We find that more than 90% of both bacterial ribosomal subunits

    更新日期:2020-10-12
  • Expanded CAG/CTG Repeats Resist Gene Silencing Mediated by Targeted Epigenome Editing
    bioRxiv. Mol. Biol. Pub Date : 2020-10-12
    Bin Yang; Alicia C. Borgeaud; Lorène Aeschbach; Oscar Rodriguez-Lima; Gustavo A Ruiz Buendia; Cinzia Cinesi; Tuncay Baubec; Vincent Dion

    Expanded CAG/CTG repeat disorders affect over 1 in 2500 individuals worldwide. Potential therapeutic avenues include gene silencing and modulation of repeat instability. However, there are major mechanistic gaps in our understanding of these processes, which prevent the rational design of an efficient treatment. To address this, we developed a novel system, ParB/ANCHOR-mediated Inducible Targeting

    更新日期:2020-10-12
  • CRISPR/Cas9-mediated generation of biallelic G0 anemonefish (Amphiprion ocellaris) mutants
    bioRxiv. Mol. Biol. Pub Date : 2020-10-11
    Laurie J Mitchell; Valerio Tettamanti; Justin N. Marshall; Karen Cheney; Fabio Cortesi

    Genomic manipulation is a useful approach for elucidating the molecular pathways underlying aspects of development, physiology, and behaviour. However, a lack of gene-editing tools appropriated for use in reef fishes has meant the genetic underpinnings for many of their unique traits remain to be investigated. One iconic group of reef fishes ideal for applying this technique are anemonefishes (Amphiprioninae)

    更新日期:2020-10-12
  • TMEM41B is a pan-flavivirus host factor
    bioRxiv. Mol. Biol. Pub Date : 2020-10-11
    H.-Heinrich Hoffmann; William M Schneider; Kathryn Rozen-Gagnon; Linde A Miles; Felix Schuster; Brandon Razooky; Eliana Jacobson; Xianfang Wu; Soon Yi; Charles M Rudin; Margaret R MacDonald; Laura K McMullan; John T Poirier; Charles M Rice

    Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication

    更新日期:2020-10-12
  • TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells
    bioRxiv. Mol. Biol. Pub Date : 2020-10-08
    Rumana Akhter; Yvonne Shao; Shane Formica; Maria Khrestian; Lynn M. Bekris

    Alzheimer's disease (AD) is characterized by the accumulation in the brain of extracellular amyloid β (Aβ) plaques as well as intraneuronal inclusions (neurofibrillary tangles) consisting of total tau and phosphorylated tau. Also present are dystrophic neurites, loss of synapses, neuronal death, and gliosis. AD genetic studies have highlighted the importance of inflammation in this disease by identifying

    更新日期:2020-10-12
  • Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress
    bioRxiv. Mol. Biol. Pub Date : 2020-10-10
    Raul Jobava; Yuanhui Mao; Bo-Jhih Guan; Dawid Krokowski; Erica Shu; Evelyn Chukwurah; Jing Wu; Zhaofeng Gao; Leah L. Zagore; William C. Merrick; Youwei Zhang; Xin Qi; Eckhard Jankowsky; Ivan Topisirovic; Donny D. Licatalosi; Shu-Bing Qian; Maria Hatzoglou

    Mammalian cells have to adapt to environmental challenges that range from mild to severe stress. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe stress conditions, cells induce a transient hibernation-like mechanism that anticipates recovery. We demonstrate that this Adaptive Pausing Response (APR)

    更新日期:2020-10-11
  • Aberrant replication licensing drives Copy Number Gains across species
    bioRxiv. Mol. Biol. Pub Date : 2020-10-10
    Patroula Nathanailidou; Michalis Petropoulos; Styliani Maxouri; Eirini Kasselimi; Ioanna Eleni Symeonidou; Ourania Preza; Iris Spiliopoulou-Sdougkou; Vladimir Benes; Stavros Taraviras; Zoi Lygerou

    Copy Number Gains (CNGs) lead to genetic heterogeneity, driving evolution and carcinogenesis. The mechanisms promoting CNG formation however remain poorly characterized. We show that abnormal expression of the replication licensing factor Cdc18 in fission yeast, which leads to genome-wide re-replication, drives the formation of CNGs at different genomic loci, promoting the acquisition of new selectable

    更新日期:2020-10-11
  • A selectable, plasmid-based system to generate CRISPR/Cas9 gene edited and knock-in mosquito cell lines
    bioRxiv. Mol. Biol. Pub Date : 2020-10-10
    Kathryn Rozen-Gagnon; Soon Yi; Eliana Jacobson; Sasha Novack; Charles M Rice

    Aedes (Ae.) aegypti and Ae. albopictus mosquitoes transmit arthropod-borne viruses (arboviruses) around the globe, causing ~700,000 deaths each year. Genetic mutants are valuable tools to interrogate both fundamental vector biology and mosquito host factors important for viral infection. However, very few genetic mutants have been described in mosquitoes in comparison to model organisms. The relative

    更新日期:2020-10-11
  • The baculovirus promoter OpIE2 sequence has inhibitory effect on the activity of the Cytomegalovirus (CMV) promoter in HeLa and HEK-293T cells
    bioRxiv. Mol. Biol. Pub Date : 2020-10-10
    Aya Aladdin; Nourhan Sahly; Rasha Faty; Mohamed Youssef; Tamer Z. Salem

    Understanding how promoters work in non-host cells is complex. Nonetheless, understanding this process is crucial while performing gene expression modulation studies. In this study, inhibitory regions in the 5' end of the OpIE2 insect viral promoter were found to be blocking the activity of the CMV promoter in mammalian cells. This finding was reached in the process of constructing a shuttle vector

    更新日期:2020-10-11
  • Evolution of the standard genetic code
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Michael Yarus

    A near-universal Standard Genetic Code (SGC) implies a single origin for Earthly life. To study this unique event, I compute paths to the SGC, comparing different plausible histories. Notably, SGC-like coding emerges from traditional evolutionary mechanisms, and a superior path can be identified. To objectively measure evolution, progress values from 0 (random coding) to 1 (SGC-like) are defined: these

    更新日期:2020-10-11
  • Evolution and origin of sliding clamp in bacteria, archaea and eukarya
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Sandesh Acharya; Amol Dahal; Hitesh Kumar Bhattarai

    Replication of DNA is an essential process in all domains of life. A protein often involved without exception in replication is the sliding clamp. The sliding clamp encircles the DNA and helps replicative polymerase stay attached to the replication machinery increasing the processivity of the polymerase. In eukaryotes and archaea the sliding clamp is called the Proliferating Cell Nuclear Antigen (PCNA)

    更新日期:2020-10-11
  • Precision Cas9 Genome Editing in vivo with All-in-one, Self-targeting AAV Vectors
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Raed Ibraheim; Phillip W. L. Tai; Aamir Mir; Nida Javeed; Jiaming Wang; Tomas C. Rodriguez; Samantha Nelson; Eraj Khokhar; Esther Mintzer; Stacy Maitland; Yueying Cao; Emmanouela Tsagkaraki; Scot A. Wolfe; Dan Wang; Athma A. Pai; Wen Xue; Guangping Gao; Erik J. Sontheimer

    Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining

    更新日期:2020-10-11
  • The VCBS superfamily, a diverse group of β-propellers that includes tachylectin and integrins
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Joana Pereira; Andrei N Lupas

    β-Propellers are found in great variety across all kingdoms of life. They assume many cellular roles, primarily as scaffolds for macromolecular interactions and catalysis. Despite their diversity, most β-propeller families clearly originated by amplification from the same ancient peptide - the β-propeller blade. In cluster analyses, β-propellers of the WD40 superfamily always formed the largest group

    更新日期:2020-10-11
  • PRC1 drives Polycomb-mediated gene repression by controlling transcription initiation and burst frequency
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Paula Dobrinić; Aleksander T. Szczurek; Robert J. Klose

    The Polycomb repressive system plays a fundamental role in controlling gene expression during mammalian development. To achieve this, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) bind target genes and use histone modification-dependent feedback mechanisms to form Polycomb chromatin domains and repress transcription. The interrelatedness of PRC1 and PRC2 activity at these sites has made it

    更新日期:2020-10-11
  • RBMX enables productive RNA processing of ultra-long exons important for genome stability
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Sara Luzzi; Gerald Hysenaj; Chileleko Siachisumo; Kathleen Cheung; Matthew R Gazzara; Katherine James; Caroline Dalgliesh; Mahsa Kheirollahi Chadegani; Ingrid Ehrmann; Graham R Smith; Simon J Cockell; Jennifer Munkley; Yoseph Barash; David J Elliott

    Previously we showed that the germline-specific RNA binding protein RBMXL2 is essential for male meiosis where it represses cryptic splicing patterns. Here we find that its ubiquitously expressed paralog RBMX helps underpin human genome stability by preventing non-productive splicing. In particular, RBMX blocks selection of aberrant splice and polyadenylation sites within some ultra-long exons that

    更新日期:2020-10-11
  • Pax7 pioneer factor action requires both paired and homeo DNA binding domains
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Audrey Pelletier; Alexandre Mayran; Arthur Gouhier; James G Omichinski; Aurelio Balsalobre; Jacques Drouin

    The pioneer transcription factor Pax7 contains two DNA binding domains (DBD), a paired and a homeo domain. Previous work on Pax7 and the related Pax3 had shown that each DBD can bind a cognate DNA sequence, thus defining two targets of binding and possibly modalities of action. Genomic targets of Pax7 pioneer action leading to chromatin opening are enriched for composite DNA target sites containing

    更新日期:2020-10-11
  • Exact p-values for global network alignments via combinatorial analysis of shared GO terms
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Wayne B. Hayes

    Network alignment aims to uncover topologically similar regions in the protein-protein interaction (PPI) networks of two or more species under the assumption that topologically similar regions perform similar functions. Although there exist a plethora of both network alignment algorithms and measures of topological similarity, currently no "gold standard" exists for evaluating how well either is able

    更新日期:2020-10-11
  • RIOK2 phosphorylation by RSK promotes synthesis of the human small ribosomal subunit
    bioRxiv. Mol. Biol. Pub Date : 2020-10-09
    Emilie L Cerezo; Thibault Houles; Oriane Lié; Marie-Kerguelen Sarthou; Charlotte Audoynaud; Genevieve Lavoie; Maral Halladjian; Sylvain Cantaloube; Carine Froment; Odile Burlet-Schiltz; Yves Henry; Philippe P Roux; Anthony Henras; Yves Romeo

    Ribosome biogenesis lies at the nexus of various signaling pathways coordinating protein synthesis with cell growth and proliferation. This process is regulated by well-described transcriptional mechanisms, but a growing body of evidence indicates that other levels of regulation exist. Here we show that the Ras/mitogen-activated protein kinase (MAPK) pathway stimulates post-transcriptional stages of

    更新日期:2020-10-11
  • Biting and resting preferences of malaria vectors in The Gambia
    bioRxiv. Mol. Biol. Pub Date : 2020-10-08
    Majidah Hamid-Adiamoh; Davis Nwakanma; Benoit Sessinou Assogba; Mamadou Ousmane Ndiath; Umberto D’Alessandro; Yaw A. Afrane; Alfred Amambua-Ngwa

    Background The scale up of indoor residual spraying and long-lasting insecticidal nets, together with other interventions have considerably reduced the malaria burden in The Gambia. This study examined the biting and resting preferences of the local insecticide-resistant vector populations. Method Indoor and outdoor-resting Anopheles gambiae mosquitoes were collected between July and October 2019 from

    更新日期:2020-10-11
  • In vivo discovery of RNA proximal proteins in human cells via proximity-dependent biotinylation
    bioRxiv. Mol. Biol. Pub Date : 2020-10-08
    Xianzhi Lin; Marcos A. S. Fonseca; Rosario I. Corona; Kate Lawrenson

    RNA molecules function as messengers or noncoding adaptor molecules, structural components, and regulators of genome organization and gene expression. Their roles and regulation are mediated by other molecules they interact with, especially RNA binding proteins (RBPs). Here we report RNA proximity labeling (RPL), an RNA-centric method based on fusion of an endonuclease-deficient Type VI CRISPR-Cas

    更新日期:2020-10-11
  • ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytes
    bioRxiv. Mol. Biol. Pub Date : 2020-10-08
    Mengjun Ma; Hongyu Li; Peng Wang; Wen Yang; Rujia Mi; Yuhang Jiang; Yixuan Lu; Xin Shen; Pengfei Sui; Yanfeng Wu; Huiyong Shen

    Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in AS patients. Firstly, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and AS patient cartilage. The pro-angiogenic

    更新日期:2020-10-11
  • Efflux mediated chlorpyrifos tolerance in Escherichia coli BL21(DE3)
    bioRxiv. Mol. Biol. Pub Date : 2020-10-08
    Aswathi Aswathi; Ashok Pandey; Rajeev K Sukumaran

    Bacteria are continually challenged with variety of synthetic chemicals/xenobiotics in their immediate surroundings, including pesticides. Chlorpyrifos (CP) is one of the most commonly used organophosphate pesticides in the world. The non-environmental strain of Escherichia coli, BL21 (DE3) displayed high tolerance to chlorpyrifos but with no/negligible degradation. The intrinsic resistance mechanisms

    更新日期:2020-10-11
  • Function expansion of antitumor transcriptional activator NFE2L1 by the original discovery of its non-transcription factor activity
    bioRxiv. Mol. Biol. Pub Date : 2020-10-08
    Qiu Lu; Yang Qiufang; Li Peng; Zhou Xiaowen; Yang Yonghui; Zhou Xiuman; Gou Shanshan; Zhai Wenjie; Li Guodong; Ren Yonggang; Zhao Wenshan; Wu Yahong; Qi Yuanming; Gao Yanfeng

    Antitumor transcription activator NFE2L1, with the functions to regulate redox homeostasis, protein turnover, and material metabolism, plays an important role in embryonic development and specialization of tissue and organ functions. Deficiency of NFE2L1 gene in different regions yields distinct phenotypes, suggesting that NFE2L1 may have a transcription factor-independent function. Here we originally

    更新日期:2020-10-11
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