A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification
Open Access
- 30 July 2007
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 204 (8), 1989-1998
- https://doi.org/10.1084/jem.20070902
Abstract
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.Keywords
This publication has 57 references indexed in Scilit:
- Contributions of ubiquitin- and PCNA-binding domains to the activity of Polymerase in Saccharomyces cerevisiaeNucleic Acids Research, 2007
- Ubiquitin-Binding Motifs in REV1 Protein Are Required for Its Role in the Tolerance of DNA DamageMolecular and Cellular Biology, 2006
- Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitinationThe Journal of cell biology, 2006
- A Role for PCNA Ubiquitination in Immunoglobulin HypermutationPLoS Biology, 2006
- Controlling the subcellular localization of DNA polymerases ι and η via interactions with ubiquitinThe EMBO Journal, 2006
- Ubiquitylation of yeast proliferating cell nuclear antigen and its implications for translesion DNA synthesisProceedings of the National Academy of Sciences of the United States of America, 2006
- The RAD6 Pathway: Control of DNA Damage Bypass and Mutagenesis by Ubiquitin and SUMOChemBioChem, 2005
- Switching from high-fidelity replicases to low-fidelity lesion-bypass polymerasesCurrent Opinion in Genetics & Development, 2004
- RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMONature, 2002
- Hypermutation of Immunoglobulin Genes in Memory B Cells of DNA Repair–deficient MiceThe Journal of Experimental Medicine, 1998