Somatic hypermutation of immunoglobulin genes in Rad18 knockout mice |
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| Institution: | 1. Department of Immunology, Kochi Medical School, Kochi University, Oko-cho Kohasu, Nankoku, Kochi 783-8505, Japan;2. Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811, Japan;3. Research Institute for Biological Sciences (RIBS), Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan;4. Departments of Gene Information Analysis, Institute for Virus Research, Kyoto University, Shogoin Kawara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan;1. National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Science, The Academy of Medical Science of Zhengzhou University, Zhengzhou, China;2. Model Animal Research Center of Nanjing University, Nanjing, China;3. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China;1. Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan;2. Laboratory of Structural Biology, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan;3. From the Departments of Biochemistry and Immunology, Preto, SP 14049-900, Brazil;4. Cell Biology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil;1. Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, United States;2. Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States;3. Department of Medicine, Stony Brook University, Stony Brook, NY 11794, United States;1. Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, No.100, Pingleyuan, Chaoyang District, Beijing 100124, China;2. National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, State Key Laboratory for Infectious Disease Prevention and Control, NO.100, YingXin Street, XiCheng District, Beijing 100032, China |
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| 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. |
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| Keywords: | Somatic hypermutation Immunoglobulin Rad18 PCNA DNA polymerase |
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