Uracil in OriS of herpes simplex 1 alters its specific recognition by origin binding protein (OBP): does virus induced uracil-DNA glycosylase play a key role in viral reactivation and replication?
We have recently demonstrated that mammalian uracil-DNA glycosylase activity is undetectable in adult neurons. On the basis of this finding we hypothesized that uracil, derived either from oxidative deamination of cytosine or misincorporation of dUMP in place of dTMP during DNA repair by the unique nuclear DNA polymerase present in adult neurons, DNA polymerase beta, might accumulate in neuronal DNA. Uracil residues could also arise in the herpes simplex 1 (HSV1) genome during latency in nerve cells. We therefore suggest a role for the virus encoded uracil-DNA glycosylase in HSV1 reactivation and in the first steps of DNA replication. We show here 1) that the viral DNA polymerase incorporates dUTP in place of dTTP with a comparable efficiency in vitro; 2) that virus specific DNA/protein interactions between the virus encoded origin binding protein and its target DNA sequence is altered by the presence of uracil residues in its central region TCGCA. Thus uracil, present in viral OriS or other key sequences could hamper the process leading to viral reactivation. Hence, HSV1 uracil-DNA glycosylase, dispensable in viral proliferation in tissue culture, could be essential in neurons for the "cleansing" of the viral genome of uracil residues before the start of replication.
Focher
F
F
Istituto di Genetica Biochimica ed Evoluzionistica, CNR, Pavia, Italy.
Verri
A
A
Verzeletti
S
S
Mazzarello
P
P
Spadari
S
S
D001483:Base Sequence; D003596:Cytosine / Q000378:metabolism; D045647:DNA Glycosylases; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D003641:Deamination; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000502:physiology*; D012093:Replicon / Q000235:genetics; D018139:Simplexvirus / Q000254:growth & development*; D013942:Thymine Nucleotides / Q000378:metabolism; D014498:Uracil / Q000378:metabolism; D051981:Uracil-DNA Glycosidase; D014764:Viral Proteins / Q000502:physiology*; D014775:Virus Activation / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology
D004268:DNA-Binding Proteins; D003856:Deoxyuracil Nucleotides; D013942:Thymine Nucleotides; D014764:Viral Proteins; C064565:UL9 protein, Human herpesvirus 1; C027078:deoxyuridine triphosphate; D014498:Uracil; D003596:Cytosine; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase; C024157:thymidine 5'-triphosphate