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¹ The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
² Microbiological Research Center-Holland bv, 1057 DN Amsterdam, Netherlands

CORRESPONDENCE Heinz Jacobs: H.Jacobs{at}nki.nl

B cells use translesion DNA synthesis (TLS) to introduce somatic mutations around genetic lesions caused by activation-induced cytidine deaminase. Monoubiquitination at lysine¹⁶⁴ of proliferating cell nuclear antigen (PCNA^K164) stimulates TLS. To determine the role of PCNA^K164 modifications in somatic hypermutation, PCNA^K164R knock-in mice were generated. PCNA^K164R/K164R mutants are born at a sub-Mendelian frequency. Although PCNA^K164R/K164R B cells proliferate and class switch normally, the mutation spectrum of hypermutated immunoglobulin (Ig) genes alters dramatically. A strong reduction of mutations at template A/T is associated with a compensatory increase at G/C, which is a phenotype similar to polymerase (Pol) and mismatch repair–deficient B cells. Mismatch recognition, monoubiquitinated PCNA, and Pol likely cooperate in establishing mutations at template A/T during replication of Ig genes.

Abbreviations used: AID, activation-induced cytidine deaminase; AnV, Annexin V; ES, embryonic stem; K, lysine; MEF, mouse embryonic fibroblast; MLPA, multiplex ligation-dependent probe amplification; MMR, mismatch repair; mRNA, messenger RNA; MSH, mutS homologue; PCNA, proliferating cell nuclear antigen; PI, propidium iodine; Pol, polymerase ; R, arginine; SHM, somatic hypermutation; SUMO, small ubiquitin-like modifier; TLS, translesion DNA synthesis; UNG2, uracil N-glycosylase 2.

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