Abstract
Cytosine deamination and the misincorporation of 2'-dUrd into DNA during replication result in the presence of uracil in DNA. Uracil-DNA glycosylases (UDGs) initiate the excision repair of this aberrant base by catalyzing the hydrolysis of the N-glycosidic bond. UDGs are expressed by nearly all known organisms, including some viruses, in which the functional role of the UDG protein remains unresolved. This issue could in principle be addressed by the availability of designed synthetic inhibitors that target the viral UDG without affecting the endogenous human UDG. Here, we report that double-stranded and single-stranded oligonucleotides incorporating either of two dUrd analogs tightly bind and inhibit the activity of herpes simplex virus type-1 (HSV-1) UDG. Both inhibitors are exquisitely specific for the HSV-1 UDG over the human UDG. These inhibitors should prove useful in structural studies aimed at understanding substrate recognition and catalysis by UDGs, as well as in elucidating the biologic role of UDGs in the life cycle of herpesviruses.
Highlights
Cytosine deamination and the misincorporation of 2dUrd into DNA during replication result in the presence of uracil in DNA
Uracil in DNA arises from the misincorporation of deoxyuridine triphosphate during replication and from the hydrolytic deamination of cytosine [1, 2]
herpes simplex virus type-1 (HSV-1) Uracil-DNA glycosylases (UDGs) is dispensable for HSV-1 replication in cell culture, presumably because the cellular UDG can supplant the activity of the viral enzyme [16, 17]
Summary
Cytosine deamination and the misincorporation of 2dUrd into DNA during replication result in the presence of uracil in DNA. This issue could in principle be addressed by the availability of designed synthetic inhibitors that target the viral UDG without affecting the endogenous human UDG. We report that double-stranded and single-stranded oligonucleotides incorporating either of two dUrd analogs tightly bind and inhibit the activity of herpes simplex virus type-1 (HSV-1) UDG.
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