Functional role, mechanism of action and exploitation of a molecular switch  Page description

Help  Print 
Back »

 

Details of project

 
Identifier
109486
Type K
Principal investigator Vértessy G., Beáta
Title in Hungarian Egy molekuláris kapcsoló szerepe, működése és felhasználási módszerei
Title in English Functional role, mechanism of action and exploitation of a molecular switch
Keywords in Hungarian represszor, nukleotid metabolizmus, DNS károsodás és javítás, génkifejeződés szabályozása, fehérje-röntgenkrisztallográfia
Keywords in English repressor, nucleotide metabolism, DNA damage and repair, regulation of gene expression, protein X-ray crystallography
Discipline
General biochemistry and metabolism (Council of Medical and Biological Sciences)50 %
Ortelius classification: Molecular biology
Structural biology (crystallography and EM) (Council of Medical and Biological Sciences)50 %
Panel Molecular and Structural Biology and Biochemistry
Department or equivalent Department of Applied Biotechnology and Food Science (Budapest University of Technology and Economics)
Participants Bakos, Vince
Békési, Angéla
Bendes, Ábris
Benedek, András
Horváth, András
Leveles, Ibolya
Liliom, Károly
Nagy, Gergely
Nyíri, Kinga
Papp-Kádár, Veronika
Rokobné Révész, Ágnes
Róna, Gergely
Scheer, Ildikó
Szabó, Judit Eszter
Tankó, Éva
Vékey, Károly
Wunderlich, Lívius
Zagyva, Imre
Starting date 2014-01-01
Closing date 2018-04-30
Funding (in million HUF) 77.580
FTE (full time equivalent) 29.93
state running project





 

Final report

 
Results in Hungarian
Az egyes fertőző betegségekért felelős mikroorganizmusok gyógyszerrezisztens törzsei egyre inkább elterjednek és széles körű rezisztenciát mutatnak a jelenleg használatos antibiotikumokkal szemben. Ezért a patogenicitási mechanizmusok vizsgálata orvosbiológiai szempontból kiemelt jelentőséggel bír. A jelen projektben a Staphylococcus aureus patogenicitási szigeteinél megvalósuló génkifejeződés szabályozásának megértésére interdiszciplináris megközelítést alkalmaztunk, state-of-the-art módszeregyüttest igénybe véve. Ezen mechanizmus során egyes virulencia és toxin faktorok különböző törzsek közötti átadására kerül sor, melynek során az eredetileg nem patogén törzsek is patogén karaktert vesznek fel. Vizsgálataink fényt derítettek ezen mechanizmus részleteire és arra is, hogy milyen módon tudjuk esetleg befolyásolni ezt az orvosbiológiai szempontból fontos folyamatot. Ezen túlmenően a DNS integritásának fenntartásában kulcsszerepet játszó dUTPáz enzimcsalád működésének szabályozására is lényegileg új útvonalat tudtunk azonosítani, egy rendkívül nagy affinitással kötődő hatékony fehérje inhibitor révén. A projekt támogatásának feltüntetésével 33 nemzetközi, referált, angol nyelvű folyóiratcikket közöltünk. Ezek közül szorosan a projekt célkitűzéseihez tartozik 21 publikáció, köztük 9 Ún D1-es folyóiratban közölt cikk (pl Nucleic Acids Research, J. Biol. Chem, Scientific Reports, J. Am Chem Soc).
Results in English
Infectious diseases present remarkable biomedical challenge due to the appearance of resistant strains of the respective causative agents. Hence, investigations into mechanisms of pathogenicity are of considerable current interest for potential medical applications. In the present project, we have employed a wide array of interdisciplinary state-of-the-art technologies to understand how gene expression regulation operates by focusing on a specific example of gene regulation in Staphylococcus. This regulation involves transmission of genomic elements that are responsible for transmission of virulence and toxin factors from pathogenic to non-pathogenic Staphylococcus strains, thereby rendering the originally non-pathogenic strains also pathogenic. Our studies revealed the molecular mechanism for this regulation and provided key insights to influence it. The results also shed light on a fully novel possibility to inhibit dUTPases, a key enzyme family responsible for keeping genomic integrity. Namely, we have identified a protein inhibitor of dUTPases that is characterized by nanomolar affinity and strong inhibitory capability. The funding for this project was acknowledged in 33 international, peer-reviewed publications. 21 publications are directly related to the aims of this project, among these 9 publications appeared in D1 journals (eg Nucleic Acids Research, J. Biol. Chem, Scientific Reports, J. Am Chem Soc).
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=109486
Decision
Yes





 

List of publications

 
Nyiri K, Mertens HDT, Tihanyi B, Nagy GN, Kohegyi B, Matejka J, Harris MJ, Szabo JE, Papp-Kadar V, Nemeth-Pongracz V, Ozohanics O, Vekey K, Svergun DI, Borysik AJ, Vertessy BG: Structural model of human dUTPase in complex with a novel proteinaceous inhibitor, SCI REP 8: (1) Paper 4326. 15 p. , 2018
Surányi ÉV, Hírmondó R, Nyíri K, Tarjányi S, Kőhegyi B, Tóth J, Vértessy BG: Exploiting a phage-bacterium interaction system as a molecular switch to decipher macromolecular interactions in the living cell, VIRUSES 10: (4) Paper 168. 13 p. , 2018
Hirmondo R, Lopata A, Suranyi EV, Vertessy BG, Toth J: Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes, SCI REP 7: (1) , 2017
Kinga Nyíri, Beáta G. Vértessy: Perturbation of genome integrity to fight pathogenic microorganisms, BBA-GEN SUBJECTS 1861: (1) pp. 3593-3612., 2017
Andras Benedek, Istvan Poloskei, Oliver Ozohanics, Karoly Vekey, Beata G Vertessy: The Stl repressor from Staphylococcus aureus is an efficient inhibitor of the eukaryotic fruitfly dUTPase, FEBS OPEN BIO 8: (2) p. 158167. 10 p. , 2018
Nikkila J, Kumar R, Campbell J, Brandsma I, Pemberton HN, Wallberg F, Nagy K, Scheer I, Vertessy BG, Serebrenik AA, Monni V, Harris RS, Pettitt SJ, Ashworth A, Lord CJ: Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells, BRIT J CANCER 117: pp. 113-123., 2017
Manikandan Periyasamy, Anup K Singh, Carolina Gemma, Christian Kranjec, Raed Farzan, Damien A Leach, Naveenan Navaratnam, Hajnalka L Pálinkás, Beata G Vértessy, Tim R Fenton, John Doorbar, Frances Fuller-Pace, David W Meek, R Charles Coombes, Laki Buluwela, Simak Ali: p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells, NUCLEIC ACIDS RES 45: (19) pp. 11056-11069., 2017
Guca E, Nagy GN, Hajdú F, Marton L, Izrael R, Hoh F, Yang Y, Vial H, Vértessy BG, Guichou JF, Cerdan R: Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis, SCI REP 25: (8) Paper 11215. 13 p. , 2018
Szalkai B, Scheer I, Nagy K, Vertessy BG, Grolmusz V: The metagenomic telescope., PLOS ONE 9: (7) e101605, 2014
Nagy GN, Leveles I, Vertessy BG: Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool., FEBS J 281: (18) 4207-4223, 2014
Anna Lopata, Pablo G Jambrina, Pankaz K Sharma, Bernard R Brooks, Judit Toth, Beata G Vertessy , Edina Rosta: Mutations Decouple Proton Transfer from Phosphate Cleavage in the dUTPase Catalytic Reaction, ACS CATAL 5: 3225-3237, 2015
Marton L, Nagy GN, Ozohanics O, Labas A, Kramos B, Olah J, Vekey K, Vertessy BG: Molecular Mechanism for the Thermo-Sensitive Phenotype of CHO-MT58 Cell Line Harbouring a Mutant CTP:Phosphocholine Cytidylyltransferase., PLOS ONE 10: (6) e0129632, 2015
Kinga Nyíri, Bianka Kőhegyi, András Micsonai, József Kardos, Beáta G Vértessy: Evidence-based structural model of the Staphylococcal repressor protein: separation of functions into different domains, PLOS ONE 10: (9), 2015
Benedek A, Horvath A, Hirmondo R, Ozohanics O, Bekesi A, Modos K, Revesz A, Vekey K, Nagy GN, Vertessy BG: Potential steps in the evolution of a fused trimeric all-beta dUTPase involve a catalytically competent fused dimeric intermediate., FEBS J 283: (18) 3268-3286, 2016
Csaba Kerepesi, Judit E Szabó, Veronika Papp-Kádár, Orsolya Dobay, Dóra Szabó, Vince Grolmusz, Beáta G Vértessy: Life without dUTPase, FRONT MICROBIOL 7:, 2016
Lopata A, Leveles I, Bendes AA, Viskolcz B, Vertessy BG, Jojart B, Toth J: A Hidden Active Site in the Potential Drug Target Mycobacterium tuberculosis dUTPase Is Accessible through Small Amplitude Protein Conformational Changes., J BIOL CHEM 291: (51) 26320-26331, 2016
Mary Christie, Chiung-Wen Chang, Gergely Róna, Kate M Smith, Alastair G Stewart, Agnes A S Takeda, Marcos R M Fontes, Murray Stewart, Vertessy BG, Jade K Forwood, Bostjan Kobe: Structural Biology and Regulation of Protein Import into the Nucleus, J MOL BIOL 428: (10) 2060-2090, 2016
Nagy GN, Suardiaz R, Lopata A, Ozohanics O, Vékey K, Brooks BR, Leveles I, Tóth J, Vértessy BG, Rosta E: Structural Characterization of Arginine Fingers: Identification of an Arginine Finger for the Pyrophosphatase dUTPases, J AM CHEM SOC 138: (45) 15035-15045, 2016
Papp-Kadar V, Szabo JE, Nyiri K, Vertessy BG: In Vitro Analysis of Predicted DNA-Binding Sites for the Stl Repressor of the Staphylococcus aureus SaPIBov1 Pathogenicity Island, PLOS ONE 11: (7), 2016
Pukancsik M, Orban A, Nagy K, Matsuo K, Gekko K, Maurin D, Hart D, Kezsmarki I, Vertessy BG: Secondary Structure Prediction of Protein Constructs Using Random Incremental Truncation and Vacuum-Ultraviolet CD Spectroscopy, PLOS ONE 11: (6), 2016
Requena CE, Perez-Moreno G, Horvath A, Vertessy BG, Ruiz-Perez LM, Gonzalez-Pacanowska D, Vidal AE: The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine., BIOCHEM J 473: (17) 2635-2643, 2016
Szabo JE, Takacs E, Merenyi G, Vertessy BG, Toth J: Trading in cooperativity for specificity to maintain uracil-free DNA., SCI REP 6:, 2016
Tóth T, Németh T, Leveles I, Vértessy BG, Huszthy P: Structural characterization of the crystalline diastereomeric complexes ..., STRUCT CHEM Article is Press: 1-8, 2016
Bartha-Vári J H, Toşa M I, Irimie F -D, Weiser D, Boros Z, Vértessy B G, Paizs C, Poppe L: Immobilization of phenylalanine ammonia-lyase on single-walled carbon nanotubes for stereoselective biotransformations in batch and in continuous-flow modes, CHEMCATCHEM 7: (7) 1122-1128, 2015
Gergely Rona, Ildiko Scheer, Kinga Nagy, Hajnalka L Palinkas, Gergely Tihanyi, Mate Borsos, Angela Bekesi, Beata G Vertessy: Detection of uracil within DNA using a sensitive labeling method for in vitro and cellular applications, NUCLEIC ACIDS RES 44, e28, 2016
Hirmondó R, Szabó JE, Nyíri K, Tarjányi S, Dobrotka P, Tóth J, Vértessy BG: Cross-species inhibition of dUTPase via the Staphylococcal Stl protein perturbs dNTP pool and colony formation in Mycobacterium, DNA REPAIR 30: 21-27, 2015
Horvath A, Batki J, Henn L, Lukacsovich T, Rona G, Erdelyi M, Vertessy BG: dUTPase expression correlates with cell division potential in Drosophila melanogaster., FEBS J 282: (10) 1998-2013, 2015
Szabó JE, Németh V, Papp-Kádár V, Nyíri K, Leveles I, Bendes AÁ, Zagyva I, Róna G, Pálinkás HL, Besztercei B, Ozohanics O, Vékey K, Liliom K, Tóth J, Vértessy BG.: Highly potent dUTPase inhibition by a bacterial repressor protein reveals a novel mechanism for gene expression control., Nucleic Acids Res. 2014 Oct 29;42(19):11912-20. doi: 10.1093/nar/gku882., 2014
Róna G, Pálinkás HL, Borsos M, Horváth A, Scheer I, Benedek A, Nagy GN, Zagyva I, Vértessy BG.: NLS copy-number variation governs efficiency of nuclear import--case study on dUTPases., FEBS J. 2014 Dec;281(24):5463-78. doi: 10.1111/febs.13086., 2014
Róna G, Borsos M, Kobe B, Vértessy BG.: Factors influencing nucleo-cytoplasmic trafficking: which matter? Response to Alvisi & Jans' comment on Phosphorylation adjacent to the nuclear localization signal of hum, Acta Crystallogr D Biol Crystallogr. 2014 Oct;70(Pt 10):2777-8. doi: 10.1107/S1399004714020501., 2014
Róna G, Borsos M, Ellis JJ, Mehdi AM, Christie M, Környei Z, Neubrandt M, Tóth J, Bozóky Z, Buday L, Madarász E, Bodén M, Kobe B, Vértessy BG.: Dynamics of re-constitution of the human nuclear proteome after cell division is regulated by NLS-adjacent phosphorylation., Cell Cycle. 2014;13(22):3551-64. doi: 10.4161/15384101.2014.960740., 2014
Anna Lopata, Pablo G Jambrina, Pankaz K Sharma, Bernard R Brooks, Judit Toth, Beata G Vertessy , Edina Rosta: Mutations Decouple Proton Transfer from Phosphate Cleavage in the dUTPase Catalytic Reaction, ACS CATAL 5: 3225-3237, 2015
Bartha-Vári J H, Toşa M I, Irimie F -D, Weiser D, Boros Z, Vértessy B G, Paizs C, Poppe L: Immobilization of phenylalanine ammonia-lyase on single-walled carbon nanotubes for stereoselective biotransformations in batch and in continuous-flow modes, CHEMCATCHEM 7: (7) 1122-1128, 2015
Gergely Rona, Ildiko Scheer, Kinga Nagy, Hajnalka L Palinkas, Gergely Tihanyi, Mate Borsos, Angela Bekesi, Beata G Vertessy: Detection of uracil within DNA using a sensitive labeling method for in vitro and cellular applications, NUCLEIC ACIDS RES 1: Article in press, 2015
Hirmondó R, Szabó JE, Nyíri K, Tarjányi S, Dobrotka P, Tóth J, Vértessy BG: Cross-species inhibition of dUTPase via the Staphylococcal Stl protein perturbs dNTP pool and colony formation in Mycobacterium, DNA REPAIR 30: 21-27, 2015
Horvath A, Batki J, Henn L, Lukacsovich T, Rona G, Erdelyi M, Vertessy BG: dUTPase expression correlates with cell division potential in Drosophila melanogaster., FEBS J 282: (10) 1998-2013, 2015
K Horváti, B Bacsa, N Szabó, K Fodor, Gy Balka, M Rusvai, É Kiss, G Mező, V Grolmusz, B Vértessy, F Hudecz, Sz Bősze: Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models, TUBERCULOSIS 95: (S1) S207-S211, 2015
Kinga Nyíri, Bianka Kőhegyi, András Micsonai, József Kardos, Beáta G Vértessy: Evidence-based structural model of the Staphylococcal repressor protein: separation of functions into different domains, PLOS ONE 10: (9) , 2015
Kinga Nyíri, Veronika Papp-Kádár, Judit E Szabó, Veronika Németh, Beáta G Vértessy: Exploring the role of the phage-specific insert of bacteriophage Φ11 dUTPase, STRUCT CHEM 26: (5) 1425-1432, 2015
Marton L, Nagy GN, Ozohanics O, Labas A, Kramos B, Olah J, Vekey K, Vertessy BG: Molecular Mechanism for the Thermo-Sensitive Phenotype of CHO-MT58 Cell Line Harbouring a Mutant CTP:Phosphocholine Cytidylyltransferase., PLOS ONE 10: (6) e0129632, 2015
Gergely N Nagy, Lívia Marton, Alicia Contet, Olivér Ozohanics, Laura-Mihaela Ardelean, Ágnes Révész, Károly Vékey, Florin Dan Irimie, Henri Vial, Rachel Cerdan, Beáta G Vértessy: Composite Aromatic Boxes for Enzymatic Transformations of Quaternary Ammonium Substrates, ANGEW CHEM INT EDIT 53: (49) 13471-13476, 2014
Judit E Szabó, Veronika Németh, Veronika Papp-Kádár, Kinga Nyíri, Ibolya Leveles, Ábris Á Bendes, Imre Zagyva, Gergely Róna, Hajnalka Pálinkás, Balázs Besztercei, Olivér Ozohanics, Károly Vékey, Károly Liliom, Judit Tóth, Beáta G Vértessy: Highly potent dUTPase inhibition by a bacterial repressor protein reveals a novel mechanism for gene expression control, NUCLEIC ACIDS RES 42: (19) 11912-11920, 2014
Nagy GN, Leveles I, Vertessy BG: Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool., FEBS J 281: (18) 4207-4223, 2014
Szalkai B, Scheer I, Nagy K, Vertessy BG, Grolmusz V: The metagenomic telescope., PLOS ONE 9: (7) e101605, 2014





 

Events of the project

 
2019-05-13 14:45:11
Résztvevők változása
2016-09-07 09:23:10
Résztvevők változása
2016-03-18 22:17:44
Résztvevők változása
2014-09-01 11:02:29
Résztvevők változása
2013-08-16 14:17:36
Résztvevők változása




Back »