Two levels of protection for the B cell genome during somatic hypermutation

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Abstract
Somatic hypermutation, the mechanism by which activated B cells in the blood produce a diversity of immunoglobulin genes giving rise to high-affinity antibodies, plays a vital role in protecting the body from infection. Yet it also represents a major risk to genomic stability, with the potential to generate B-cell tumours if unchecked or wrongly directed. The somatic hypermutation reaction is initiated by activation induced deaminase (AID), and it is widely assumed that the risk of inappropriate hypermutation is averted by careful targeting of this enzyme. New work in mice suggests that this is not the case. Rather, AID deaminates a large fraction of the expressed genome, including numerous oncogenes linked to B-cell malignancies. Widespread mutation of the genome is averted in a surprising manner: by gene-specific, error-free DNA repair mediated by base excision and mismatch repair. Somatic hypermutation introduces point mutations into immunoglobulin genes in germinal centre B cells during an immune response. The reaction is initiated by cytosine deamination by the activation-induced deaminase (AID) and completed by error-prone processing of the resulting uracils by mismatch and base excision repair factors1. Somatic hypermutation represents a threat to genome integrity2 and it is not known how the B cell genome is protected from the mutagenic effects of somatic hypermutation nor how often these protective mechanisms fail. Here we show, by extensive sequencing of murine B cell genes, that the genome is protected by two distinct mechanisms: selective targeting of AID and gene-specific, high-fidelity repair of AID-generated uracils. Numerous genes linked to B cell tumorigenesis, including Myc, Pim1, Pax5, Ocab (also called Pou2af1), H2afx, Rhoh and Ebf1, are deaminated by AID but escape acquisition of most mutations through the combined action of mismatch and base excision repair. However, approximately 25% of expressed genes analysed were not fully protected by either mechanism and accumulated mutations in germinal centre B cells. Our results demonstrate that AID acts broadly on the genome, with the ultimate distribution of mutations determined by a balance between high-fidelity and error-prone DNA repair.