PARI deficiency leads to increased somatic hypermutation

Somatic hypermutation of immunoglobulin (Ig) genes in germinal center B cells is based on the introduction of DNA lesions by activation-induced cytidine deaminase (AID), followed by lesion processing by multiple error-prone DNA repair pathways. Error-free DNA repair by homologous recombination (HR) is required for the repair of lesions introduced into non-Ig genes. Recently, we have shown that HR is also required for efficient mutagenesis in Ig genes, likely by facilitating survival of cells with high rates of mutagenesis. Here, we have investigated the effects of inactivation of the HR inhibitor PARI on somatic hypermutation. We find that PARI-deficient B cells show normal proliferation upon activation and class switching. The germinal center reaction is also unperturbed in PARI knockout mice. However, mutagenesis at the Ig locus is significantly increased in PARI-deficient mice, suggesting that increased mutagenic capacity is associated with increased HR capacity. Furthermore, mutagenesis at the non-Ig genes CD83 and Bcl-6 is significantly increased in the absence of PARI. Accordingly, germinal center B cells must maintain a fine balance of HR capacity to allow high mutagenesis at Ig genes but limited mutagenesis at AID off-targets.