The Journal of Experimental Medicine
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Published online July 30, 2007
doi:10.1084/jem.20070902
The Journal of Experimental Medicine, Vol. 204, No. 8, 1989-1998
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Langerak et al.
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ARTICLE

 A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification

Petra Langerak1, Anders O.H. Nygren2, Peter H.L. Krijger1, Paul C.M. van den Berk1, and Heinz Jacobs1

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 (PCNAK164) stimulates TLS. To determine the role of PCNAK164 modifications in somatic hypermutation, PCNAK164R knock-in mice were generated. PCNAK164R/K164R mutants are born at a sub-Mendelian frequency. Although PCNAK164R/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 {eta} (Pol{eta}) and mismatch repair–deficient B cells. Mismatch recognition, monoubiquitinated PCNA, and Pol{eta} 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{eta}, polymerase {eta}; R, arginine; SHM, somatic hypermutation; SUMO, small ubiquitin-like modifier; TLS, translesion DNA synthesis; UNG2, uracil N-glycosylase 2.


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