The translesion DNA polymerase θ plays a dominant role in immunoglobulin gene somatic hypermutation

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Abstract
Immunoglobulin (Ig) somatic hypermutation (SHM) critically underlies the generation of high‐affinity antibodies. Mutations can be introduced by error‐prone polymerases such as polymerase ζ (Rev3), a mispair extender, and polymerase η, a mispair inserter with a preference for dA/dT, while repairing DNA lesions initiated by AID‐mediated deamination of dC to yield dU:dG mismatches. The partial impairment of SHM observed in the absence of these polymerases led us to hypothesize a main role for another translesion DNA polymerase. Here, we show that deletion in C57BL/6J mice of the translesion polymerase θ, which possesses a dual nucleotide mispair inserter–extender function, results in greater than 60% decrease of mutations in antigen‐selected V186.2DJH transcripts and greater than 80% decrease in mutations in the Ig H chain intronic JH4‐iEμ sequence, together with significant alterations in the spectrum of the residual mutations. Thus, polymerase θ plays a dominant role in SHM, possibly by introducing mismatches while bypassing abasic sites generated by UDG‐mediated deglycosylation of AID‐effected dU, by extending DNA past such abasic sites and by synthesizing DNA during dU:dG mismatch repair.