Initiation of DNA replication: lessons from viral initiator proteins

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Abstract
Initiator proteins recognize and bind to the replicator and serve to initiate DNA replication. The activities that are provided by initiator proteins range from recognition of the ori and recruitment of replication factors, to melting of double-stranded DNA and replicative DNA-helicase activity. A surprising feature of initiator proteins is that they bind DNA with modest sequence specificity, although marking of the site of initiation is a task that is likely to require high specificity. For viral initiator proteins, the low specificity is caused by the presence of a nonspecific DNA-binding activity that is required for the melting and unwinding steps. Highly specific binding for ori recognition is generated by inhibition of the nonspecific binding activity. DNA-binding domains, which direct site-specific DNA binding of initiator proteins, are structurally related in initiators from different virus groups and demonstrate a common ancestry of these domains with proteins that bind RNA. Viral initiator proteins, using multiple protein–DNA and protein–protein interactions, assemble in an ordered fashion into different complexes that, in succession, provide sequence-specific recognition, DNA-melting activity and DNA-helicase activity. This 'hardwiring' of the successive initiator activities ensures a highly efficient and robust initiation process. We suggest that one way to understand the complex cellular initiator proteins is to understand in some detail how viral initiators function: such an understanding will assist in the identification and characterization of the corresponding functions that are present in the cellular initiators.