Ubiquitylated PCNA plays a role in somatic hypermutation and class-switch recombination and is required for meiotic progression

Sergio Roa, Elena Avdievich, Jonathan U. Peled, Thomas MacCarthy, Uwe Werling, Li Kuang Fei, Rui Kan, Chunfang Zhao, Aviv Bergman, Paula E. Cohen, Winfried Edelmann, Matthew D. Scharff

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73 Scopus citations

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 -/-tgK164R) 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-η (Polη), 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 -/-tgK164R 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).

Original languageEnglish (US)
Pages (from-to)16248-16253
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number42
DOIs
StatePublished - Oct 21 2008

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