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Supplementary materials, information Supplementary Table S1. List of GO terms used for the networks COVID-19, chloroquine and arrhythmia markers. Supplementary Table S2. List of the nodes of intersection of COVID-19 and chloroquine (264 nodes) and ACE2/TMPRSS2 and chloroquine (2 nodes). Supplementary Figure S1. Network generated with the targets of chloroquine (A) and biological processes represented by that network (B). The network was built with Cytoscape and UniProt database. Biological processes were retrieved with BiNGO tool. Supplementary Figure S2. Network generated with the targets of COVID-19 (A) and biological processes represented by that network (B). The network was built with Cytoscape and UniProt database. Biological processes were retrieved with BiNGO tool. Supplementary Figure S3. Network generated with the targets of ACE2 and TMPRSS2 (A) and biological processes represented by that network (B). The network was built with Cytoscape and UniProt database. Biological processes were retrieved with BiNGO tool. Supplementary Figure S4. Network generated with the targets of arrhytmia (A) and biological processes represented by that network (B). The network was built with Cytoscape and UniProt database. Biological processes were retrieved with BiNGO tool. Supplementary File S1. Cytoscape Session file (.cys) contains networks used in this study. These networks can be evaluated for nodes and edges of interest, e.g. to see identifiers. See the text for annotation of the networks. The file is uploaded at FigShare for free access; link is https://figshare.com/articles/online_resource/SupplementaryFileS1_Cytoscape_DataNetwork_cy s/12793580 . Supplementary Figure S1 B A 1336 nodes, 2526 edges 1224 biological processes Supplementary Figure S2 A B 828 nodes, 1545 edges 721 biological processes Supplementary Figure S3 A B 231 biological processes 15 nodes, 19 edges Supplementary Figure S4 B A 63 nodes, 80 edges 641 biological processes Supplementary Table S1. Lists of nodes used in this study for building networks. A) Targets of chloroquine GSTA2, TNF, TLR9, GST, HMGB1, GSTM1, CYP2C8, CYP3A4, CYP3A5, CYP2D6, CYP1A1 B) COVID-19 interacting proteins AP3B1, BRD4, BRD2, CWC27, ZC3H18, SLC44A2, PMPCB, YIF1A, ATP1B1, ACADM, ETFA, STOM, GGCX, ATP6V1A, PSMD8, REEP5, PMPCA, ANO6, PITRM1, SLC30A9, FASTKD5, SLC30A7, TUBGCP3, COQ8B, SAAL1, REEP6 , INTS4, SLC25A21, TUBGCP2, TARS2, RTN4, FAM8A1, AASS, AKAP8L, AAR2, BZW2, RRP9, PABPC1, CSNK2A2, CSNK2B, G3BP1, PABPC4, LARP1, FAM98A, SNIP1, UPF1, MOV10, G3BP2, DDX21, RBM28, RPL36, GOLGA7, ZDHHC5, POLA1, PRIM1, PRIM2, POLA2, COLGALT1, PKP2, AP2A2, GFER, ERGIC1, AP2M1, GRPEL1, TBCA, SBNO1, BCKDK, AKAP8, MYCBP2, SLU7, RIPK1, UBAP2L, TYSND1, PDZD11, PRRC2B, UBAP2, ZNF318, CRTC3, USP54, ZC3H7A, LARP4B, RBM41, TCF12, PPIL3, PLEKHA5, TBKBP1, CIT, HSBP1, PCNT, CEP43, PRKAR2A, PRKACA, PRKAR2B, RDX, CENPF, TLE1, TLE3, TLE5, GOLGA3, GOLGA2, GOLGB1, GRIPAP1, CEP350, PDE4DIP, CEP135, CEP68, CNTRL, ERC1, GCC2, CLIP4, NIN, CEP112, MIPOL1, USP13, GCC1, JAKMIP1, CDK5RAP2, AKAP9, GORASP1, FYCO1, C1orf50, CEP250, TBK1, HOOK1, NINL, GLA, IMPDH2, SIRT5, NUTF2, ARF6, RNF41, SLC27A2, EIF4E2, POR, RAP1GDS1, WASHC4, FKBP15, GIGYF2, IDE, TIMM10, ALG11, NUP210, TIMM29, DNAJC11, TIMM10B, TIMM9, HDAC2, GPX1, TRMT1, ATP5MG, ATP6AP1, SIGMAR1, ATP13A3, AGPS, CYB5B, ACSL3, CYB5R3, RALA, COMT, RAB5C, RAB7A, RAB8A, RAB2A, RAB10, RAB14, RHOA, RAB1A, GNB1, GNG5, LMAN2, MOGS, TOR1AIP1, MTARC1, QSOX2, HS2ST1, NDUFAF2, SCCPDH, SCARB1, NAT14, DCAKD, FAM162A, DNAJC19, SELENOS, PTGES2, RAB18, MPHOSPH10, SRP72, ATE1, NSD2, SRP19, SRP54, MRPS25, DDX10, LARP7, MEPCE, NGDN, EXOSC8, NARS2, NOL10, CCDC86, SEPSECS, EXOSC5, EXOSC3, AATF, HECTD1, MRPS2, MRPS5, EXOSC2, MRPS27, GTF2F2, FBN1, FBN2, NUP214, NUP62, DCAF7, EIF4H, NUP54, MIB1, SPART, NEK9, ZNF503, NUP88, NUP58, MAT2B, FBLN5, PPT1, CUL2, MAP7D1, THTPA, ZYG11B, TIMM8B, RBX1, ELOC, ELOB, HMOX1, TRIM59, ARL6IP6, VPS39, CLCC1, VPS11, SUN2, ALG5, STOML2, NUP98, RAE1, MTCH1, HEATR3, MDN1, PLOD2, TOR1A, STC2, PLAT, ITGB1, CISD3, COL6A1, PVR, DNMT1, LOX, PCSK6, INHBE, NPC2, MFGE8, OS9, NPTX1, POGLUT2, POGLUT3, ERO1B, PLD3, FOXRED2, CHPF, PUSL1, EMC1, GGH, ERLEC1, IL17RA, NGLY1, HS6ST2, SDF2, NEU1, GDF15, TM2D3, ERP44, EDEM3, SIL1, POFUT1, SMOC1, PLEKHF2, FBXL12, UGGT2, CHPF2, ADAMTS1, HYOU1, FKBP7, ADAM9, FKBP10, SLC9A3R1, CHMP2A, CSDE1, TOMM70, MARK3, MARK2, DPH5, DCTPP1, MARK1, PTBP2, BAG5, UBXN8, GPAA1, WFS1, ABCC1, F2RL1, SCAP, DPY19L1, TMEM97, SLC30A6, TAPT1, ERMP1, NLRX1, RETREG3, PIGO, FAR2, ECSIT, ALG8, TMEM39B, GHITM, ACAD9, NDFIP2, BCS1L, NDUFAF1, TMED5, NDUFB9, PIGS C) Markers of arrhythmia OPN, ANXA5, GDF15, MPO, LGALS3, TNNT2, TNNI3, ANFB, REN, IL6, CRP Supplementary Table S2 Intersection nodes of Chloroquine and COVID‐19 networks. The listed are 266 nodes that are common for the networks formed by chloroquine and COVID‐19. The rows from 3 to 266 show the nodes of COVID‐19 network, and the last 2 rows annotate ACE2/TMPRSS2 common nodes, ALB and YWHAZ. Common nodes of Chloroquine and Covid19 networks Accession Name Human number Label P09429 High mobility group box 1 HMGB1 P12004 Proliferating cell nuclear antigen PCNA Q9Y3U8 Ribosomal protein L36 RPL36 Q9Y2W1 Thyroid hormone receptor associated protein 3 THRAP3 Q9NYF8 BCL2 associated transcription factor 1 BCLAF1 Q9H307 Pinin, desmosome associated protein PNN Q8NEJ9 Neuroguidin NGDN Q86VM9 Zinc finger CCCH‐type containing 18 ZC3H18 Q6PKG0 La ribonucleoprotein 1, translational regulator LARP1 Q15287 RNA binding protein with serine rich domain 1 RNPS1 Q13573 SNW domain containing 1 SNW1 Q09161 Nuclear cap binding protein subunit 1 NCBP1 P62913 Ribosomal protein L11 RPL11 P62753 Ribosomal protein S6 kinase B1 RPS6 P62424 Ribosomal protein L7A RPL7A P38919 Eukaryotic translation initiation factor 4A3 EIF4A3 P23396 Ribosomal protein S3 RPS3 P19338 Nucleolin NCL Q07021 Complement C1q binding protein C1QBP P42858 Huntingtin HTT P12682 High mobility group box 1 HMGB1 Q9QUN7 Toll like receptor 2 Tlr2 P63158 High mobility group box 1 Hmgb1 O00206 Toll like receptor 4 TLR4 Q9QUK6 Toll like receptor 4 Tlr4 Q8TDQ0 Hepatitis A virus cellular receptor 2 HAVCR2 P43405 Spleen associated tyrosine kinase SYK Q9NP31 SH2 domain containing 2A SH2D2A P60484 Phosphatase and tensin homolog PTEN CHEBI:16755 CHEBI:16755 P22366 MYD88 innate immune signal transduction adaptor Myd88 O60260 Parkin RBR E3 ubiquitin protein ligase PRKN Q7Z434 Mitochondrial antiviral signaling protein MAVS O95786 DExD/H‐box helicase 58 DDX58 1 Q9BYX4 Interferon induced with helicase C domain 1 IFIH1 O15111 Component of inhibitor of nuclear factor kappa B kinase CHUK complex O14920 Inhibitor of nuclear factor kappa B kinase subunit beta IKBKB P35637 FUS RNA binding protein FUS Q08211 DExH‐box helicase 9 DHX9 P10636‐8 Microtubule associated protein tau MAPT EBI‐14348029 EBI‐ 14348029 Q05127 Polymerase complex protein VP35 Q9HCE5 Methyltransferase like 14 METTL14 Q9R1S0 B9 domain containing 1 B9d1 P55085 F2R like trypsin receptor 1 F2RL1 Q9UBU9 Nuclear RNA export factor 1 NXF1 Q28141 DExH‐box helicase 9 DHX9 P61286 Poly(A) binding protein cytoplasmic 1 PABPC1 Q9QXM1 Junction mediating and regulatory protein, p53 cofactor JMY P07602 Prosaposin PSAP Q14164 Inhibitor of nuclear factor kappa B kinase subunit epsilon IKBKE P04487 Tegument protein US11 [Human alphaherpesvirus 1 US11 Q9H7S9 Zinc finger protein 703 ZNF703 F1BA49 B303_sSgp2 nonstructural protein [ SFTS virus HB29 ] F1BA49 O75569 Protein activator of interferon induced protein kinase PRKRA EIF2AK2 Q9UHD2 TANK binding kinase 1 TBK1 Q9NZ43 Unconventional SNARE in the ER 1 USE1 Q86U44 Methyltransferase like 3 METTL3 O00571 DEAD‐box helicase 3 X‐linked DDX3X O35658 Complement C1q binding protein C1qbp Q9NVI7 ATPase family AAA domain containing 3A ATAD3A Q5T9A4 ATPase family AAA domain containing 3B ATAD3B O14730 RIO kinase 3 RIOK3 O14672 ADAM metallopeptidase domain 10 ADAM10 P49768 Presenilin 1 PSEN1 P05067‐ Amyloid beta precursor protein APP PRO_0000000092 Q8N6Q3 CD177 CD177 P05067‐8 Amyloid beta precursor protein APP P49755 Transmembrane p24 trafficking protein 10 TMED10 Q8N766 ER membrane protein complex subunit 1 EMC1 Q04637 Eukaryotic translation initiation factor 4 gamma 1 EIF4G1 P54253 Ataxin 1 ATXN1 Q923E4 Sirtuin 1 Sirt1 P34902 Interleukin 2 receptor subunit gamma Il2rg 2 P07750 Interleukin 4 Il4 Q9NQC3 Reticulon 4 RTN4 Q16820 Meprin A subunit beta MEP1B O00213 Amyloid beta precursor protein binding family B member 1 APBB1 Q9Y6D5 ADP ribosylation factor guanine nucleotide exchange factor ARFGEF2 2 P19438 TNF receptor superfamily member 1A TNFRSF1A Q9ULZ3 PYD and CARD domain containing PYCARD Q13546 Receptor interacting serine/threonine kinase 1 RIPK1 P48729 Casein kinase 1 alpha 1 CSNK1A1 Q06A28 Ribonucleoside‐diphosphate reductase large subunit RIR1 Q60855 Receptor interacting serine/threonine kinase 1 Ripk1 Q9Y6K9 Inhibitor of nuclear factor kappa B kinase regulatory IKBKG subunit gamma O70343 PPARG coactivator 1 alpha Ppargc1a Q9UBK2 PPARG coactivator 1 alpha PPARGC1A Q9DBR0 A‐kinase anchoring protein 8 Akap8 P25799 Nuclear factor kappa B subunit 1 Nfkb1 O43823 A‐kinase anchoring protein 8 AKAP8 P42574 Caspase 3 CASP3 Q12933 TNF receptor associated factor 2 TRAF2 Q9UQ80 Proliferation‐associated 2G4 PA2G4 Q92769 Histone deacetylase 2 HDAC2 Q9Z2D8 Methyl‐CpG binding domain protein 3 Mbd3 Q6NYC1 Jumonji domain containing 6, arginine demethylase and JMJD6 lysine hydroxylase P04156 Prion protein PRNP Q06124 Protein tyrosine phosphatase non‐receptor type 11 PTPN11 Q01101 INSM transcriptional repressor 1 INSM1 O88895 Histone
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  • Molecular Genetics of Microcephaly Primary Hereditary: an Overview

    Molecular Genetics of Microcephaly Primary Hereditary: an Overview

    brain sciences Review Molecular Genetics of Microcephaly Primary Hereditary: An Overview Nikistratos Siskos † , Electra Stylianopoulou †, Georgios Skavdis and Maria E. Grigoriou * Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece; [email protected] (N.S.); [email protected] (E.S.); [email protected] (G.S.) * Correspondence: [email protected] † Equal contribution. Abstract: MicroCephaly Primary Hereditary (MCPH) is a rare congenital neurodevelopmental disorder characterized by a significant reduction of the occipitofrontal head circumference and mild to moderate mental disability. Patients have small brains, though with overall normal architecture; therefore, studying MCPH can reveal not only the pathological mechanisms leading to this condition, but also the mechanisms operating during normal development. MCPH is genetically heterogeneous, with 27 genes listed so far in the Online Mendelian Inheritance in Man (OMIM) database. In this review, we discuss the role of MCPH proteins and delineate the molecular mechanisms and common pathways in which they participate. Keywords: microcephaly; MCPH; MCPH1–MCPH27; molecular genetics; cell cycle 1. Introduction Citation: Siskos, N.; Stylianopoulou, Microcephaly, from the Greek word µικρoκεϕαλi´α (mikrokephalia), meaning small E.; Skavdis, G.; Grigoriou, M.E. head, is a term used to describe a cranium with reduction of the occipitofrontal head circum- Molecular Genetics of Microcephaly ference equal, or more that teo standard deviations
  • Scaffolding During the Cell Cycle by A-Kinase Anchoring Proteins

    Scaffolding During the Cell Cycle by A-Kinase Anchoring Proteins

    Pflugers Arch - Eur J Physiol DOI 10.1007/s00424-015-1718-0 INVITED REVIEW Scaffolding during the cell cycle by A-kinase anchoring proteins B. Han1,2 & W. J. Poppinga1,2 & M. Schmidt1,2 Received: 12 May 2015 /Revised: 28 June 2015 /Accepted: 1 July 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Cell division relies on coordinated regulation of the specific AKAP subset in relation to diseases with focus on a cell cycle. A process including a well-defined series of strictly diverse subset of cancer. regulated molecular mechanisms involving cyclin-dependent kinases, retinoblastoma protein, and polo-like kinases. Dys- Keywords AKAPs . Scaffolding . Cell cycle . Proliferation . functions in cell cycle regulation are associated with disease Cancer such as cancer, diabetes, and neurodegeneration. Compart- mentalization of cellular signaling is a common strategy used to ensure the accuracy and efficiency of cellular responses. Introduction Compartmentalization of intracellular signaling is maintained by scaffolding proteins, such as A-kinase anchoring proteins The growth of organisms is driven by cell division which (AKAPs). AKAPs are characterized by their ability to anchor relies on coordinated regulation of phases in cell cycle [4]. the regulatory subunits of protein kinase A (PKA), and there- When the cell is quiescent, it remains in the G1 phase; how- by achieve guidance to different cellular locations via various ever, on initiation of cell division, it progresses into the S targeting domains. Next to PKA, AKAPs also associate with phase, during which DNA replication occurs, followed by a several other signaling elements including receptors, ion chan- separation of sister chromatids during the M phase, which in nels, protein kinases, phosphatases, small GTPases, and phos- turn is again separated in the pro-, meta-, ana-, and telophase, phodiesterases.
  • Genomic Discovery of an Evolutionarily Programmed Modality for Small-Molecule Targeting of an Intractable Protein Surface

    Genomic Discovery of an Evolutionarily Programmed Modality for Small-Molecule Targeting of an Intractable Protein Surface

    Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface Uddhav K. Shigdela,1,2, Seung-Joo Leea,1,3, Mathew E. Sowaa,1,4, Brian R. Bowmana,1,5, Keith Robisona,6, Minyun Zhoua,7, Khian Hong Puaa,8, Dylan T. Stilesa,6, Joshua A. V. Blodgetta,9, Daniel W. Udwarya,10, Andrew T. Rajczewskia,11, Alan S. Manna,12, Siavash Mostafavia,13, Tara Hardyb, Sukrat Aryab,14, Zhigang Wenga,15, Michelle Stewarta,16, Kyle Kenyona,6, Jay P. Morgensterna,6, Ende Pana,17, Daniel C. Graya,6, Roy M. Pollocka,4, Andrew M. Fryb, Richard D. Klausnerc,18, Sharon A. Townsona,19, and Gregory L. Verdinea,d,e,f,2,18,20 Contributed by Richard D. Klausner, April 21, 2020 (sent for review April 8, 2020; reviewed by Chuan He and Ben Shen) The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional Author contributions: U.K.S., S.-J.L., M.E.S., B.R.B., K.R., Z.W., M.S., D.C.G., R.M.P., A.M.F., R.D.K., S.A.T., and G.L.V. designed research; U.K.S., S.-J.L., M.E.S., K.R., M.Z., K.H.P., D.T.S., therapeutic modalities are needed to overcome this deficiency. J.A.V.B., D.W.U., A.T.R., A.S.M., S.M., T.H., S.A., K.K., J.P.M., E.P., R.D.K., and G.L.V. performed Here, the identification and characterization of a natural product, research; M.E.S., D.T.S., and A.M.F.
  • Polo-Like Kinase 1 Regulates Nlp, a Centrosome Protein Involved in Microtubule Nucleation

    Polo-Like Kinase 1 Regulates Nlp, a Centrosome Protein Involved in Microtubule Nucleation

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Cell, Vol. 5, 113–125, July, 2003, Copyright 2003 by Cell Press Polo-like Kinase 1 Regulates Nlp, a Centrosome Protein Involved in Microtubule Nucleation Martina Casenghi,1,2 Patrick Meraldi,1,2,3 Rieder, 1999; Palazzo et al., 2000). Although centrosome Ulrike Weinhart,1 Peter I. Duncan,1,4 maturation is important for mitotic spindle formation, the Roman Ko¨ rner,1 and Erich A. Nigg1,* underlying mechanisms remain largely unknown. Two 1Department of Cell Biology protein kinases, Polo-like kinase 1 (Plk1; Lane and Nigg, Max Planck Institute of Biochemistry 1996; Sunkel and Glover, 1988) and Aurora-A (Berdnik Am Klopferspitz 18a and Knoblich, 2002; Hannak et al., 2001), as well as D-82152 Martinsried protein phosphatase 4 (Helps et al., 1998; Sumiyoshi Germany et al., 2002), have been implicated in the regulation of centrosome maturation, but the substrates of these en- zymes await identification. Also acting at the G2/M tran- sition, the protein kinase Nek2 and a member of the Summary phosphatase 1 family contribute to regulate centrosome separation, in part through phosphorylation of the centri- In animal cells, most microtubules are nucleated at ole-associated protein C-Nap1 (Fry et al., 1998b; Helps centrosomes. At the onset of mitosis, centrosomes et al., 2000; Mayor et al., 2000). undergo a structural reorganization, termed matura- The discovery of ␥-tubulin and ␥-tubulin-containing tion, which leads to increased microtubule nucleation multiprotein complexes has greatly advanced our un- activity.