Hoogsteen base pair formation promotes synthesis opposite the 1,N ⁶-ethenodeoxyadenosine lesion by human DNA polymerase ι

The 1,N⁶-ethenodeoxyadenosine (εdA) lesion is promutagenic and has been implicated in carcinogenesis. We show here that human Polι, a Y-family DNA polymerase, can promote replication through this lesion by proficiently incorporating a nucleotide opposite it. The structural basis of this action is rotation of the εdA adduct to the syn conformation in the Polι active site and presentation of its 'Hoogsteen edge' for hydrogen-bonding with incoming dTTP or dCTP. We also show that Polζ carries out the subsequent extension reaction and that efficiency of extension from εdA•T is notably higher than from εdA•C. Together, our studies reveal for the first time how the exocyclic εdA adduct is accommodated in a DNA polymerase active site, and they show that the combined action of Polι and Polζ provides for efficient and error-free synthesis through this potentially carcinogenic DNA lesion.