On page 1191, Delbos and colleagues provide the first proof that the error-prone polymerase η (polη) is responsible for mutations at A-T base pairs during somatic hypermutation (SHM) of immunoglobulin (Ig) genes in mice. But when polη is removed from mice, another sloppy enzyme, not previously thought to contribute to SHM, can fill in as a pinch hitter.
SHM generates high affinity antibodies in response to antigenic challenge; it does so by introducing point mutations into the antigen-binding regions of B cell antibody genes. Mutations at C-G base pairs during SHM are the work of the enzyme AID (activation-induced cytidine deaminase), which turns cytosine into uracil. A-T mutations have been harder to explain. Error-prone polymerases are thought be the culprits behind A-T mutation, but specific roles for these enzymes have been difficult to assign, as mice lacking individual polymerases have thus far shown no defects in SHM.
Polη has been the primary suspect charged with mutating A-T base pairs, as the pattern of errors made by polη in vitro is reminiscent of that seen in mutated Ig loci. In addition, humans lacking polη have fewer A-T mutations in their Ig genes than normal. Delbos et al. now solidify the evidence by showing that elimination of polη in mice decreases Ig gene mutations at A-T base pairs.
The few A-T mutations that occurred in the absence of polη—to the authors' surprise—bore the signature of another polymerase, polκ, which does not normally meddle in SHM. The authors suggest that the mismatch repair protein complex MSH2–MSH6, recently shown to recruit polη to AID-induced U-G mismatches, may in polη's absence instead bind polκ. The polκ would then cause mutations at nearby A-T sites.