Suppressors

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József Burgyán - One of the best experts on this subject based on the ideXlab platform.

  • viral silencing Suppressors: Tools forged to fine-tune host-pathogen coexistence.
    Virology, 2015
    Co-Authors: Tibor Csorba, Levente Kontra, József Burgyán
    Abstract:

    RNA silencing is a homology-dependent gene inactivation mechanism that regulates a wide range of biological processes including antiviral defense. To deal with host antiviral responses viruses evolved mechanisms to avoid or counteract this, most notably through expression of viral Suppressors of RNA silencing. Besides working as silencing Suppressors, these proteins may also fulfill other functions during infection. In many cases the interplay between the suppressor function and other "unrelated" functions remains elusive. We will present host factors implicated in antiviral pathways and summarize the current status of knowledge about the diverse viral Suppressors' strategies acting at various steps of antiviral silencing in plants. Besides, we will consider the multi-functionality of these versatile proteins and related biochemical processes in which they may be involved in fine-tuning the plant-virus interaction. Finally, we will present the current applications and discuss perspectives of the use of these proteins in molecular biology and biotechnology.

  • small rna binding is a common strategy to suppress rna silencing by several viral Suppressors
    The EMBO Journal, 2006
    Co-Authors: Lorant Lakatos, Tibor Csorba, Vitantonio Pantaleo, Elisabeth J Chapman, James C Carrington, Yu Ping Liu, Valerian V Dolja, Lourdes Fernandez Calvino, Juan Jose Lopezmoya, József Burgyán
    Abstract:

    RNA silencing is an evolutionarily conserved system that functions as an antiviral mechanism in higher plants and insects. To counteract RNA silencing, viruses express silencing Suppressors that interfere with both siRNA- and microRNA-guided silencing pathways. We used comparative in vitro and in vivo approaches to analyse the molecular mechanism of suppression by three well-studied silencing Suppressors. We found that silencing Suppressors p19, p21 and HC-Pro each inhibit the intermediate step of RNA silencing via binding to siRNAs, although the molecular features required for duplex siRNA binding differ among the three proteins. None of the Suppressors affected the activity of preassembled RISC complexes. In contrast, each suppressor uniformly inhibited the siRNA-initiated RISC assembly pathway by preventing RNA silencing initiator complex formation.

Stephen P Jackson - One of the best experts on this subject based on the ideXlab platform.

  • detection of functional protein domains by unbiased genome wide forward genetic screening
    Scientific Reports, 2018
    Co-Authors: Mareike Herzog, Fabio Puddu, Julia Coates, Nicola J Geisler, Josep V Forment, Stephen P Jackson
    Abstract:

    Establishing genetic and chemo-genetic interactions has played key roles in elucidating mechanisms by which certain chemicals perturb cellular functions. In contrast to gene disruption/depletion strategies to identify mechanisms of drug resistance, searching for point-mutational genetic Suppressors that can identify separation- or gain-of-function mutations has been limited. Here, by demonstrating its utility in identifying chemical-genetic Suppressors of sensitivity to the DNA topoisomerase I poison camptothecin or the poly(ADP-ribose) polymerase inhibitor olaparib, we detail an approach allowing systematic, large-scale detection of spontaneous or chemically-induced suppressor mutations in yeast or haploid mammalian cells in a short timeframe, and with potential applications in other haploid systems. In addition to applications in molecular biology research, this protocol can be used to identify drug targets and predict drug-resistance mechanisms. Mapping suppressor mutations on the primary or tertiary structures of protein suppressor hits provides insights into functionally relevant protein domains. Importantly, we show that olaparib resistance is linked to missense mutations in the DNA binding regions of PARP1, but not in its catalytic domain. This provides experimental support to the concept of PARP1 trapping on DNA as the prime source of toxicity to PARP inhibitors, and points to a novel olaparib resistance mechanism with potential therapeutic implications.

  • detection of functional protein domains by unbiased genome wide forward genetic screening
    bioRxiv, 2017
    Co-Authors: Mareike Herzog, Fabio Puddu, Julia Coates, Nicola J Geisler, Josep V Forment, Stephen P Jackson
    Abstract:

    Genetic and chemo-genetic interactions have played key roles in elucidating the molecular mechanisms by which certain chemicals perturb cellular functions. Many studies have employed gene knockout collections or gene disruption/depletion strategies to identify routes for evolving resistance to chemical agents. By contrast, searching for point-mutational genetic Suppressors that can identify separation- or gain-of-function mutations, has been limited even in simpler, genetically amenable organisms such as yeast, and has not until recently been possible in mammalian cell culture systems. Here, by demonstrating its utility in identifying Suppressors of cellular sensitivity to the drugs camptothecin or olaparib, we describe an approach allowing systematic, large-scale detection of spontaneous or chemically-induced suppressor mutations in yeast and in haploid mouse embryonic stem cells in a short timeframe, and with potential applications in essentially any other haploid system. In addition to its utility for molecular biology research, this protocol can be used to identify drug targets and to predict mechanisms leading to drug resistance. Mapping suppressor mutations on the primary sequence or three-dimensional structures of protein suppressor hits provides insights into functionally relevant protein domains, advancing our molecular understanding of protein functions, and potentially helping to improve drug design and applicability.

Shigetou Namba - One of the best experts on this subject based on the ideXlab platform.

  • a dual strategy for the suppression of host antiviral silencing two distinct Suppressors for viral replication and viral movement encoded by potato virus m
    Journal of Virology, 2011
    Co-Authors: Hiroko Senshu, Yasuyuki Yamaji, Nami Minato, Takuya Shiraishi, Kensaku Maejima, Masayoshi Hashimoto, Chihiro Miura, Yutaro Neriya, Shigetou Namba
    Abstract:

    Viruses encode RNA silencing Suppressors to counteract host antiviral silencing. In this study, we analyzed the Suppressors encoded by potato virus M (PVM), a member of the genus Carlavirus. In the conventional green fluorescent protein transient coexpression assay, the cysteine-rich protein (CRP) of PVM inhibited both local and systemic silencing, whereas the triple gene block protein 1 (TGBp1) showed suppressor activity only on systemic silencing. Furthermore, to elucidate the roles of these two Suppressors during an active viral infection, we performed PVX vector-based assays and viral movement complementation assays. CRP increased the accumulation of viral RNA at the single-cell level and also enhanced viral cell-to-cell movement by inhibiting RNA silencing. However, TGBp1 facilitated viral movement but did not affect viral accumulation in protoplasts. These data suggest that CRP inhibits RNA silencing primarily at the viral replication step, whereas TGBp1 is a suppressor that acts at the viral movement step. Thus, our findings demonstrate a sophisticated viral infection strategy that suppresses host antiviral silencing at two different steps via two mechanistically distinct Suppressors. This study is also the first report of the RNA silencing suppressor in the genus Carlavirus.

  • variability in the level of rna silencing suppression caused by triple gene block protein 1 tgbp1 from various potexviruses during infection
    Journal of General Virology, 2009
    Co-Authors: Hiroko Senshu, Ken Komatsu, Johji Ozeki, Satoshi Kagiwada, Yasuyuki Yamaji, Masayoshi Hashimoto, Kouji Hatada, Michiko Aoyama, Shigetou Namba
    Abstract:

    RNA silencing is an important defence mechanism against virus infection, and many plant viruses encode RNA silencing Suppressors as a counter defence. In this study, we analysed the RNA silencing suppression ability of multiple virus species of the genus Potexvirus. Nicotiana benthamiana plants exhibiting RNA silencing of a green fluorescent protein (GFP) transgene showed reversal of GFP fluorescence when systemically infected with potexviruses. However, the degree of GFP fluorescence varied among potexviruses. Agrobacterium-mediated transient expression assay in N. benthamiana leaves demonstrated that the triple gene block protein 1 (TGBp1) encoded by these potexviruses has drastically different levels of silencing suppressor activity, and these differences were directly related to variations in the silencing suppression ability during virus infection. These results suggest that suppressor activities differ even among homologous proteins encoded by viruses of the same genus, and that TGBp1 contributes to the variation in the level of RNA silencing suppression by potexviruses. Moreover, we investigated the effect of TGBp1 encoded by Plantago asiatica mosaic virus (PlAMV), which exhibited a strong suppressor activity, on the accumulation of microRNA, virus genomic RNA and virus-derived small interfering RNAs.

Masaru Niki - One of the best experts on this subject based on the ideXlab platform.

  • identification of dok genes as lung tumor Suppressors
    Nature Genetics, 2010
    Co-Authors: Alice H Berger, Masaru Niki, Alessandro Morotti, Barry S Taylor, Nicholas D Socci, Agnes Viale
    Abstract:

    Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor Suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor Suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor.

Alessandro Morotti - One of the best experts on this subject based on the ideXlab platform.

  • identification of dok genes as lung tumor Suppressors
    Nature Genetics, 2010
    Co-Authors: Alice H Berger, Masaru Niki, Alessandro Morotti, Barry S Taylor, Nicholas D Socci, Agnes Viale
    Abstract:

    Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor Suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor Suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor.