A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification.
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 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 eta (Poleta) and mismatch repair-deficient B cells. Mismatch recognition, monoubiquitinated PCNA, and Poleta likely cooperate in establishing mutations at template A/T during replication of Ig genes.
The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Petra
P
Langerak
Anders O H
AO
Nygren
Peter H L
PH
Krijger
Paul C M
PC
van den Berk
Heinz
H
Jacobs
D000225:Adenine / Q000737:chemistry*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D003596:Cytosine / Q000737:chemistry*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005786:Gene Expression Regulation; D006720:Homozygote; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D008954:Models, Biological; D016296:Mutagenesis; D009154:Mutation; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics* / Q000502:physiology*; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism
D007136:Immunoglobulins; D018809:Proliferating Cell Nuclear Antigen; D025801:Ubiquitin; D003596:Cytosine; C407743:DNA polymerase mu; D004259:DNA-Directed DNA Polymerase; D000225:Adenine