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Journal of Virology, April 2004, p. 4278-4288, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4278-4288.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Ribonucleotide Reductase R1 Homolog of Murine Cytomegalovirus Is Not a Functional Enzyme Subunit but Is Required for Pathogenesis{dagger}

David Lembo,1* Manuela Donalisio,1 Anders Hofer,2 Maura Cornaglia,1 Wolfram Brune,3 Ulrich Koszinowski,4 Lars Thelander,2 and Santo Landolfo1

Department of Public Health and Microbiology, University of Turin, Turin, Italy,1 Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden,2 Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg,3 Max von Pettenkofer Institute, Munich, Germany4

Received 23 September 2003/ Accepted 5 December 2003

Ribonucleotide reductase (RNR) is the key enzyme in the biosynthesis of deoxyribonucleotides. Alpha- and gammaherpesviruses express a functional enzyme, since they code for both the R1 and the R2 subunits. By contrast, betaherpesviruses contain an open reading frame (ORF) with homology to R1, but an ORF for R2 is absent, suggesting that they do not express a functional RNR. The M45 protein of murine cytomegalovirus (MCMV) exhibits the sequence features of a class Ia RNR R1 subunit but lacks certain amino acid residues believed to be critical for enzymatic function. It starts to be expressed independently upon the onset of viral DNA synthesis at 12 h after infection and accumulates at later times in the cytoplasm of the infected cells. Moreover, it is associated with the virion particle. To investigate direct involvement of the virally encoded R1 subunit in ribonucleotide reduction, recombinant M45 was tested in enzyme activity assays together with cellular R1 and R2. The results indicate that M45 neither is a functional equivalent of an R1 subunit nor affects the activity or the allosteric control of the mouse enzyme. To replicate in quiescent cells, MCMV induces the expression and activity of the cellular RNR. Mutant viruses in which the M45 gene has been inactivated are avirulent in immunodeficient SCID mice and fail to replicate in their target organs. These results suggest that M45 has evolved a new function that is indispensable for virus replication and pathogenesis in vivo.

* Corresponding author. Mailing address: Department of Public Health and Microbiology, University of Turin, Via Santena, 9, 10126 Turin, Italy. Phone: 39-011-6706608. Fax: 39-011-6636436. E-mail: david.lembo{at}unito.it.

{dagger} This work is dedicated to the memory of Giorgio Cavallo.

Journal of Virology, April 2004, p. 4278-4288, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4278-4288.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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