DNA polymerase θ accomplishes translesion synthesis opposite 1, N6-ethenodeoxyadenosine with a remarkably high fidelity in human cells

Here we show that translesion synthesis (TLS) opposite 1, N-6-ethenodeoxyadenosine (edA), which disrupts Watson-Crick base pairing, occurs via Pol iota/Pol zeta-, Rev1-, and Pol theta-dependent pathways. The requirement of Pol iota/Pol zeta is consistent with the ability of Pol iota to incorporate nucleotide opposite epsilon dA by Hoogsteen base pairing and of Pol zeta to extend synthesis. Rev1 polymerase and Pol theta conduct TLS opposite epsilon dA via alternative error-prone pathways. Strikingly, in contrast to extremely error-prone TLS opposite epsilon dA by purified Pol theta, it performs predominantly error-free TLS in human cells. Reconfiguration of the active site opposite epsilon dA would provide Pol theta the proficiency for error-free TLS in human cells.