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

• DOI: 10.1084/jem.20070902
• Publication Date: 2007-07-31T00:59:37Z
• Authors: Petra Langerak; Anders O.H. Nygren; Peter H.L. Krijger; Paul C.M. van den...; Heinz Jacobs
• Keywords: 0301 basic medicine; B-Lymphocytes; Ubiquitin; Adenine; Homozygote; Immunoglobulins; Articles; DNA-Directed DNA Polymerase; Models, Biological; 3. Good health; Cytosine; Mice; 03 medical and health sciences; Phenotype; Gene Expression Regulation; Mutagenesis; Proliferating Cell Nuclear Antigen; Mutation; Animals; Cell Proliferation

B cells use translesion DNA synthesis (TLS) to introduce somatic mutations around genetic lesions caused by activation-induced cytidine deaminase. Monoubiquitination at lysine(164) of proliferating cell nuclear antigen (PCNA(K164)) stimulates TLS. To determine the role PCNA(K164) modifications in hypermutation, PCNA(K164R) knock-in mice were generated. PCNA(K164R/K164R) mutants are born a sub-Mendelian frequency. Although proliferate and class switch normally, mutation spectrum hypermutated immunoglobulin (Ig) genes alters dramatically. A strong reduction template A/T is associated with compensatory increase G/C, which phenotype similar polymerase eta (Poleta) mismatch repair-deficient cells. Mismatch recognition, monoubiquitinated PCNA, Poleta likely cooperate establishing during replication Ig genes.