An RNA virus hijacks an incognito function of a DNA repair enzyme.
A previously described mammalian cell activity, called VPg unlinkase, specifically cleaves a unique protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection. For over three decades, the identity of this cellular activity and its normal role in the uninfected cell had remained elusive. Here we report the purification and identification of VPg unlinkase as the DNA repair enzyme, 5'-tyrosyl-DNA phosphodiesterase-2 (TDP2). Our data show that VPg unlinkase activity in different mammalian cell lines correlates with their differential expression of TDP2. Furthermore, we show that recombinant TDP2 can cleave the protein-RNA linkage generated by different picornaviruses without impairing the integrity of viral RNA. Our results reveal a unique RNA repair-like function for TDP2 and suggest an unusual role in host-pathogen interactions for this cellular enzyme. On the basis of the identification of TDP2 as a potential antiviral target, our findings may lead to the development of universal therapeutics to treat the millions of individuals afflicted annually with diseases caused by picornaviruses, including myocarditis, aseptic meningitis, encephalitis, hepatitis, and the common cold.
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA 92697, USA.
Richard
R
Virgen-Slane
Janet M
JM
Rozovics
Kerry D
KD
Fitzgerald
Tuan
T
Ngo
Wayne
W
Chou
Gerbrand J
GJ
van der Heden van Noort
Dmitri V
DV
Filippov
Paul D
PD
Gershon
Bert L
BL
Semler
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D019143:Evolution, Molecular; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D010849:Picornaviridae / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; D014764:Viral Proteins; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human