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Journal articleMaertens GNE, 2016,
B'-protein phosphatase 2A is a functional binding partner of delta-retroviral integrase
, Nucleic Acids Research, Vol: 44, Pages: 364-376, ISSN: 1362-4962To establish infection, a retrovirus must insert a DNA copy of its RNA genome into host chromatin. This reaction is catalysed by the virally encoded enzyme integrase (IN) and is facilitated by viral genus-specific host factors. Herein, cellular serine/threonine protein phosphatase 2A (PP2A) is identified as a functional IN binding partner exclusive to δ-retroviruses, including human T cell lymphotropic virus type 1 and 2 (HTLV-1 and HTLV-2) and bovine leukaemia virus (BLV). PP2A is a heterotrimer composed of a scaffold, catalytic and one of any of four families of regulatory subunits, and the interaction is specific to the B′ family of the regulatory subunits. B′-PP2A and HTLV-1 IN display nuclear co-localization, and the B′ subunit stimulates concerted strand transfer activity of δ-retroviral INs in vitro. The protein–protein interaction interface maps to a patch of highly conserved residues on B′, which when mutated render B′ incapable of binding to and stimulating HTLV-1 and -2 IN strand transfer activity.
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Journal articleLong J, Efstathios SG, Moncorge O, et al., 2016,
Species difference in ANP32A underlies influenza A virus polymerase host restriction
, Nature, Vol: 529, Pages: 101-104, ISSN: 1476-4687Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans1. Host range breaches are limited by incompatibilities between avian virus components and the human host. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells2. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown3, 4, 5, 6. We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the leucine-rich repeats and carboxy-terminal low-complexity acidic region domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian-adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity, whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2(E627K), were rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the shorter mammalian ANP32A. Thus ANP32A represents an essential host partner co-opted to support influenza virus replication and is a candidate host target for novel antivirals.
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Journal articleSenavirathne G, Bertram JG, Jaszczur M, et al., 2015,
Activation-induced deoxycytidine deaminase (AID) co-transcriptional scanning at single-molecule resolution
, Nature Communications, Vol: 6, ISSN: 2041-1723Activation-induced deoxycytidine deaminase (AID) generates antibody diversity in B cells by initiating somatic hypermutation (SHM) and class-switch recombination (CSR) during transcription of immunoglobulin variable (IgV) and switch region (IgS) DNA. Using single-molecule FRET, we show that AID binds to transcribed dsDNA and translocates unidirectionally in concert with RNA polymerase (RNAP) on moving transcription bubbles, while increasing the fraction of stalled bubbles. AID scans randomly when constrained in an 8 nt model bubble. When unconstrained on single-stranded (ss) DNA, AID moves in random bidirectional short slides/hops over the entire molecule while remaining bound for ~5 min. Our analysis distinguishes dynamic scanning from static ssDNA creasing. That AID alone can track along with RNAP during transcription and scan within stalled transcription bubbles suggests a mechanism by which AID can initiate SHM and CSR when properly regulated, yet when unregulated can access non-Ig genes and cause cancer.
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Journal articleKoutsakos M, Thi HN, Barclay WS, et al., 2015,
Knowns and unknowns of influenza B viruses
, Future Microbiology, Vol: 11, Pages: 119-135, ISSN: 1746-0913Influenza B viruses (IBVs) circulate annually along with influenza A (IAV) strains during seasonal epidemics. IBV can dominate influenza seasons and cause severe disease, particularly in children and adolescents. Research has revealed interesting aspects of IBV and highlighted the importance of these viruses in clinical settings. Yet, many important questions remain unanswered. In this review, the clinical relevance of IBV is emphasized, unique features in epidemiology, host range and virology are highlighted and gaps in knowledge pinpointed. Multiple aspects of IBV epidemiology, evolution, virology and immunology are discussed. Future research into IBV is needed to understand how we can prevent severe disease in high-risk groups, especially children and elderly.
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Journal articleBrenlla A, Rueda D, Romano LJ, 2015,
Mechanism of aromatic amine carcinogen bypass by the Y-family polymerase, Dpo4
, Nucleic Acids Research, Vol: 43, Pages: 9918-9927, ISSN: 1362-4962 -
Journal articleHardin JW, Warnasooriya C, Kondo Y, et al., 2015,
Assembly and dynamics of the U4/U6 di-snRNP by single-molecule FRET
, Nucleic Acids Research, ISSN: 1362-4962 -
Journal articleMatos-Patron A, Byrd-Leotis L, Steinhauer DA, et al., 2015,
Amino acid substitution D222N from fatal influenza infection affects receptor-binding properties of the influenza A(H1N1)pdm09 virus
, VIROLOGY, Vol: 484, Pages: 15-21, ISSN: 0042-6822- Author Web Link
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Journal articleLiu M, Lam MK-H, Zhang Q, et al., 2015,
The Functional Study of the N-Terminal Region of Influenza B Virus Nucleoprotein
, PLOS One, Vol: 10, ISSN: 1932-6203Influenza nucleoprotein (NP) is a major component of the ribonucleoprotein (vRNP) in influenzavirus, which functions for the transcription and replication of viral genome. Comparedto the nucleoprotein of influenza A (ANP), the N-terminal region of influenza B nucleoprotein(BNP) is much extended. By virus reconstitution, we found that the first 38 residues areessential for viral growth. We further illustrated the function of BNP by mini-genome reconstitution,fluorescence microscopy, electron microscopy, light scattering and gel shift.Results show that the N terminus is involved in the formation of both higher homo-oligomersof BNP and BNP-RNA complex.
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Journal articleGregorovic G, Boulden EA, Bosshard R, et al., 2015,
Epstein-Barr viruses deficient in EBER RNAs give higher LMP2 RNA expression in lymphoblastoid cell lines and efficiently establish persistent infection in humanized mice.
, Journal of Virology, Vol: 89, Pages: 1171-11714, ISSN: 1098-5514Functions of EBER RNAs were tested in lymphoblastoid cell lines containing EBER mutants of Epstein-Barr Virus (EBV). Binding of EBER1 to RPL22 was confirmed. Deletion of EBER1 or EBER2 correlated with increased cytoplasmic EBV LMP2 RNA and with small effects on specific cellular miRNA levels but protein levels of LMP1 and LMP2A were not affected. Wild type and EBER deletion EBV had approximately equal ability to infect immunodeficient mice reconstituted with a human haematopoietic system.
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Journal articleMcCallin AJ, Maertens GN, Bangham CRM, 2015,
Host determinants of HTLV-1 integration site preference
, RETROVIROLOGY, Vol: 12, ISSN: 1742-4690
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