Translesion synthesis (TLS) by Y-family DNA polymerases is a chief mechanism of DNA damage tolerance¹. Such TLS can be accurate or error-prone, as it is for bypass of a cyclobutane pyrimidine dimer by DNA polymerase (XP-V or Rad30) or bypass of a (6-4) TT photoproduct by DNA polymerase V (UmuD'₂C), respectively^{2, 3}. Although DinB is the only Y-family DNA polymerase conserved among all domains of life, the biological rationale for this striking conservation has remained enigmatic⁴. Here we report that the Escherichia colidinB gene is required for resistance to some DNA-damaging agents that form adducts at the N²-position of deoxyguanosine (dG). We show that DinB (DNA polymerase IV) catalyses accurate TLS over one such N²-dG adduct (N²-furfuryl-dG), and that DinB and its mammalian orthologue, DNA polymerase , insert deoxycytidine (dC) opposite N²-furfuryl-dG with 10–15-fold greater catalytic proficiency than opposite undamaged dG. We also show that mutating a single amino acid, the 'steric gate' residue of DinB (Phe13 Val) and that of its archaeal homologue Dbh (Phe12 Ala), separates the abilities of these enzymes to perform TLS over N²-dG adducts from their abilities to replicate an undamaged template. We propose that DinB and its orthologues are specialized to catalyse relatively accurate TLS over some N²-dG adducts that are ubiquitous in nature, that lesion bypass occurs more efficiently than synthesis on undamaged DNA, and that this specificity may be achieved at least in part through a lesion-induced conformational change.

1. Department of Chemistry,
2. Department of Biology, and
3. Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
4. *These authors contributed equally to this work

Correspondence to: Graham C. Walker² Correspondence and requests for materials should be addressed to G.C.W. (Email: gwalker@mit.edu).

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