Somatic hypermutation of immunoglobulin genes: lessons from proliferating cell nuclear antigen super(K164R) mutant mice

• Published in: Philosophical transactions of the Royal Society of London. Series B. Biological sciences Vol. 364; no. 1517; pp. 621 - 629
• Main Authors: Langerak, Petra, Krijger, Peter HL, Heideman, Marinus R, Van den Berk, Paul CM, Jacobs, Heinz
• Format: Journal Article
• Language: English
• Published: 12.03.2009
• ISSN: 0962-8436; 1471-2970
• DOI: 10.1098/rstb.2008.0223

Proliferating cell nuclear antigen (PCNA) encircles DNA as a ring-shaped homotrimer and, by tethering DNA polymerases to their template, PCNA serves as a critical replication factor. In contrast to high-fidelity DNA polymerases, the activation of low-fidelity translesion synthesis (TLS) DNA polymerases seems to require damage-inducible monoubiquitylation (Ub) of PCNA at lysine residue 164 (PCNA-Ub). TLS polymerases can tolerate DNA damage, i.e. they can replicate across DNA lesions. The lack of proofreading activity, however, renders TLS highly mutagenic. The advantage is that B cells use mutagenic TLS to introduce somatic mutations in immunoglobulin (Ig) genes to generate high-affinity antibodies. Given the critical role of PCNA- Ub in activating TLS and the role of TLS in establishing somatic mutations in immunoglobulin genes, we analysed the mutation spectrum of somatically mutated immunoglobulin genes in B cells from PCNA super(K164R) knock-in mice. A 10-fold reduction in A/T mutations is associated with a compensatory increase in G/C mutations-a phenotype similar to PolI* and mismatch repair-deficient B cells. Mismatch recognition, PCNA-Ub and PolI* probably act within one pathway to establish the majority of mutations at template A/T. Equally relevant, the G/C mutator(s) seems largely independent of PCNA super(K164) modification.