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...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	The Journal of experimental medicine Jg. 206; H. 12; S. 2603
Hauptverfasser:	Krijger, Peter H L, Langerak, Petra, van den Berk, Paul C M, Jacobs, Heinz
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 23.11.2009
Schlagworte:	Animals Antibody Affinity - physiology B-Lymphocytes - immunology B-Lymphocytes - metabolism Mice Mice, Mutant Strains Mutation - immunology MutS Homolog 2 Protein - genetics MutS Homolog 2 Protein - immunology MutS Homolog 2 Protein - metabolism Proliferating Cell Nuclear Antigen - genetics Proliferating Cell Nuclear Antigen - immunology Proliferating Cell Nuclear Antigen - metabolism Somatic Hypermutation, Immunoglobulin - physiology Ubiquitinated Proteins - genetics Ubiquitinated Proteins - immunology Ubiquitinated Proteins - metabolism Uracil-DNA Glycosidase - genetics Uracil-DNA Glycosidase - immunology Uracil-DNA Glycosidase - metabolism
ISSN:	1540-9538, 1540-9538
Online-Zugang:	Weitere Angaben
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1540-9538 1540-9538
DOI:	10.1084/jem.20091707