Vaccinia virus-encoded ribonucleotide reductase subunits are differentially required for replication and pathogenesis.

PLoS Pathogens
Don B GammonDavid H Evans

Abstract

Ribonucleotide reductases (RRs) are evolutionarily-conserved enzymes that catalyze the rate-limiting step during dNTP synthesis in mammals. RR consists of both large (R1) and small (R2) subunits, which are both required for catalysis by the R1(2)R2(2) heterotetrameric complex. Poxviruses also encode RR proteins, but while the Orthopoxviruses infecting humans [e.g. vaccinia (VACV), variola, cowpox, and monkeypox viruses] encode both R1 and R2 subunits, the vast majority of Chordopoxviruses encode only R2 subunits. Using plaque morphology, growth curve, and mouse model studies, we investigated the requirement of VACV R1 (I4) and R2 (F4) subunits for replication and pathogenesis using a panel of mutant viruses in which one or more viral RR genes had been inactivated. Surprisingly, VACV F4, but not I4, was required for efficient replication in culture and virulence in mice. The growth defects of VACV strains lacking F4 could be complemented by genes encoding other Chordopoxvirus R2 subunits, suggesting conservation of function between poxvirus R2 proteins. Expression of F4 proteins encoding a point mutation predicted to inactivate RR activity but still allow for interaction with R1 subunits, caused a dominant negative phenotype in ...Continue Reading

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Citations

Oct 7, 2011·Journal of Virology·Li QinDavid H Evans
Apr 20, 2012·Journal of Virology·Chad R Irwin, David H Evans
Feb 15, 2013·Journal of Virology·Wondimagegnehu M TeferiDavid H Evans
Jul 5, 2013·PLoS Pathogens·Joseph A HollenbaughBaek Kim
Oct 16, 2013·Antimicrobial Agents and Chemotherapy·Sophie DuraffourRobert Snoeck
Nov 26, 2015·Human Gene Therapy·Georges VassauxPierre Cordelier
Oct 29, 2013·Journal of Molecular Biology·Alexandre SzeJohn Hiscott
Mar 13, 2012·Antiviral Research·Mark N Prichard, Earl R Kern
Nov 26, 2014·Human Gene Therapy·Marion GayralPierre Cordelier
Aug 18, 2012·Advances in Urology·Kyle G PottsRonald B Moore
Aug 15, 2014·PLoS Pathogens·Nicholas van BuurenMichele Barry
Jan 24, 2014·PLoS Pathogens·Carolina S IlkowJean-Simon Diallo
Jul 9, 2016·The Journal of General Virology·Mark A O'DeaChris Upton
May 17, 2012·Viruses·Jun Kurita, Kazuhiro Nakajima
Sep 9, 2017·Viruses·Chad SmithsonChris Upton
Feb 28, 2014·Journal of Virology·Li Qin, David H Evans
Mar 18, 2019·Medical Microbiology and Immunology·Catharina MajerRenate König
Nov 30, 2018·Frontiers in Microbiology·Amina Cherif LouazaniBernard La Scola
Apr 17, 2020·Expert Opinion on Biological Therapy·Adrian PelinRagunath Singaravelu
Dec 15, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Clare Y SlaneyMichael H Kershaw
Apr 4, 2021·Cancers·Laura Evgin, Richard G Vile
Aug 17, 2021·Chemical Society Reviews·Joshua T McLeanEoin M Scanlan

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Datasets Mentioned

BETA
BAD12267.1
AAO89322.1

Methods Mentioned

BETA
co-immunoprecipitation
immunoprecipitation
immunoprecipitations
ubiquitination
interaction studies
transfections
scraping
transfection
PCR

Software Mentioned

ClustalW
ZEN
ImageJ
ProSci
ImageQuant
Adobe Photoshop
GraphPad Prism

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