Dependence of nucleotide substitutions on Ung2, Msh2, and PCNA-Ub during somatic hypermutation.
During somatic hypermutation (SHM), B cells introduce mutations into their immunoglobulin genes to generate high affinity antibodies. Current models suggest a separation in the generation of G/C transversions by the Ung2-dependent pathway and the generation of A/T mutations by the Msh2/ubiquitinated proliferating cell nuclear antigen (PCNA-Ub)-dependent pathway. It is currently unknown whether these pathways compete to initiate mutagenesis and whether PCNA-Ub functions downstream of Ung2. Furthermore, these models do not explain why mice lacking Msh2 have a more than twofold reduction in the total mutation frequency. Our data indicate that PCNA-Ub is required for A/T mutagenesis downstream of both Msh2 and Ung2. Furthermore, we provide evidence that both pathways are noncompetitive to initiate mutagenesis and even collaborate to generate half of all G/C transversions. These findings significantly add to our understanding of SHM and necessitate an update of present SHM models.
Krijger
Peter H L
PH
Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
Langerak
Petra
P
van den Berk
Paul C M
PC
Jacobs
Heinz
H
D000818:Animals; D000915:Antibody Affinity / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation / Q000276:immunology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D027041:Somatic Hypermutation, Immunoglobulin / Q000502:physiology*; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D018809:Proliferating Cell Nuclear Antigen; D057149:Ubiquitinated Proteins; D051981:Uracil-DNA Glycosidase; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein