Title |
Ubiquitylated PCNA plays a role in somatic hypermutation and class-switch recombination and is required for meiotic progression
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Published in |
Proceedings of the National Academy of Sciences of the United States of America, October 2008
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DOI | 10.1073/pnas.0808182105 |
Pubmed ID | |
Authors |
Sergio Roa, Elena Avdievich, Jonathan U. Peled, Thomas MacCarthy, Uwe Werling, Fei Li Kuang, Rui Kan, Chunfang Zhao, Aviv Bergman, Paula E. Cohen, Winfried Edelmann, Matthew D. Scharff |
Abstract |
Somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes are dependent upon activation-induced cytidine deaminase (AID)-induced mutations. The scaffolding properties of proliferating cell nuclear antigen (PCNA) and ubiquitylation of its residue K164 have been suggested to play an important role organizing the error-prone repair events that contribute to the AID-induced diversification of the Ig locus. We generated knockout mice for PCNA (Pcna(-/-)), which were embryonic lethal. Expression of PCNA with the K164R mutation rescued the lethal phenotype, but the mice (Pcna(-/-)tg(K164R)) displayed a meiotic defect in early pachynema and were sterile. B cells proliferated normally in Pcna(-/-)tg(K164R) mice, but a PCNA-K164R mutation resulted in impaired ex vivo CSR to IgG1 and IgG3, which was associated with reduced mutation frequency at the switch regions and a bias toward blunt junctions. Analysis of the heavy chain V186.2 region after NP-immunization showed in Pcna(-/-)tg(K164R) mice a significant reduction in the mutation frequency of A:T residues in WA motifs preferred by polymerase-eta (Poleta), and a strand-biased increase in the mutation frequency of G residues, preferentially in the context of AID-targeted GYW motifs. The phenotype of Pcna(-/-)tg(K164R) mice supports the idea that ubiquitylation of PCNA participates directly in the meiotic process and the diversification of the Ig locus through class-switch recombination (CSR) and somatic hypermutation (SHM). |
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Vietnam | 1 | 1% |
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Readers by professional status | Count | As % |
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Student > Ph. D. Student | 19 | 23% |
Student > Master | 7 | 8% |
Student > Bachelor | 7 | 8% |
Student > Doctoral Student | 5 | 6% |
Other | 14 | 17% |
Unknown | 10 | 12% |
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Philosophy | 1 | 1% |
Other | 4 | 5% |
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