Somatic hypermutation of immunoglobulin genes: lessons from proliferating cell nuclear antigenK164R mutant mice.
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 PCNAK164R 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 Poleta and mismatch repair-deficient B cells. Mismatch recognition, PCNA-Ub and Poleta 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 PCNAK(164) modification.
Langerak
Petra
P
The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Krijger
Peter H L
PH
Heideman
Marinus R
MR
van den Berk
Paul C M
PC
Jacobs
Heinz
H
D000818:Animals; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D009713:Nucleotidyltransferases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics* / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D054875:Ubiquitination; D000099270:Y-Family DNA Polymerases
D004259:DNA-Directed DNA Polymerase; D009713:Nucleotidyltransferases; D018809:Proliferating Cell Nuclear Antigen; C496086:Rev1 protein, mouse; D000099270:Y-Family DNA Polymerases