The DNA of all living systems is under constant assault by a variety of agents that if not repaired present severe blockages to normal replication machinery. Cells have evolved mechanisms to traverse these lesions through specialized polymerases referred to as the bypass or Y-family DNA polymerases. The human's Y-family polymerases, Pol eta, Pol iota, have been shown to replicate through a variety of DNA lesions. Pol eta, for example, is unique in its ability to replicate through a UV-induced cis-syn Thymine- Tymine dimer efficiently and accurately [6]. Mutations in human Pol eta are responsible for the inherited, cancer-prone syndrome, the variant form of xeroderma pigmentosum (XP-V). Unlike Pol eta, Pol iota is unable to replicate through a cis-syn T-T dimer. Pol iota, however, can insert a nucleotide opposite 3'T of a UV-induced 6-4 photoproduct, but is unable to carry out the subsequent extension steps [17]. To understand the underlying mechanism of how each of these bypass DNA polymerases is able to replicate past UV-induced lesions, I propose to elucidate the structures of the above-mentioned polymerases with both UV photoproducts.
