title: Somatic hypermutation of immunoglobulin genes in Rad18 knockout mice.
abstract: Somatic hypermutation (SHM) of immunoglobulin (Ig) genes is triggered by the activity of activation-induced cytidine deaminase (AID). AID induces DNA lesions in variable regions of Ig genes, and error-prone DNA repair mechanisms initiated in response to these lesions introduce the mutations that characterize SHM. Error-prone DNA repair in SHM is proposed to be mediated by low-fidelity DNA polymerases such as those that mediate trans-lesion synthesis (TLS); however, the mechanism by which these enzymes are recruited to AID-induced lesions remains unclear. Proliferating cell nuclear antigen (PCNA), the sliding clamp for multiple DNA polymerases, undergoes Rad6/Rad18-dependent ubiquitination in response to DNA damage. Ubiquitinated PCNA promotes the replacement of the replicative DNA polymerase stalled at the site of a DNA lesion with a TLS polymerase. To examine the potential role of Rad18-dependent PCNA ubiquitination in SHM, we analyzed Ig gene mutations in Rad18 knockout (KO) mice immunized with T cell-dependent antigens. We found that SHM in Rad18 KO mice was similar to wild-type mice, suggesting that Rad18 is dispensable for SHM. However, residual levels of ubiquitinated PCNA were observed in Rad18 KO cells, indicating that Rad18-independent PCNA ubiquitination might play a role in SHM.
authors.affiliation: Department of Immunology, Kochi Medical School, Kochi University, Oko-cho Kohasu, Nankoku, Kochi 783-8505, Japan. Electronic address: tshimizu@kochi-u.ac.jp.
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tateishi
authors.affiliation: Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanoue
authors.affiliation: Research Institute for Biological Sciences (RIBS), Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan.
authors.forename: Takachika
authors.initials: T
authors.lastname: Azuma
authors.affiliation: Departments of Gene Information Analysis, Institute for Virus Research, Kyoto University, Shogoin Kawara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Ohmori
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; C485954:RAD18 protein, human; D004247:DNA; D044767:Ubiquitin-Protein Ligases; D004259:DNA-Directed DNA Polymerase
keywords: DNA polymerase; Immunoglobulin; PCNA; Rad18; Somatic hypermutation