E1 initiator DNA binding specificity is unmasked by selective inhibition of non-specific DNA binding

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Abstract
Initiator proteins are critical components of the DNA replication machinery and mark the site of initiation. This activity probably requires highly selective DNA binding; however, many initiators display modest specificity in vitro . We demonstrate that low specificity of the papillomavirus E1 initiator results from the presence of a non‐specific DNA‐binding activity, involved in melting, which masks the specificity intrinsic to the E1 DNA‐binding domain. The viral factor E2 restores specificity through a physical interaction with E1 that suppresses non‐specific binding. We propose that this arrangement, where one DNA‐binding activity tethers the initiator to ori while another alters DNA structure, is a characteristic of other viral and cellular initiator proteins. This arrangement would provide an explanation for the low selectivity observed for DNA binding by initiator proteins.