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

Proc Natl Acad Sci U S A 2008 Oct 14;105(42):16248-53. Epub 2008 Oct 14.

Departments of Cell Biology and Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

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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http://dx.doi.org/10.1073/pnas.0808182105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2571010PMC
October 2008
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References

(Supplied by CrossRef)

Di Noia et al.
Annual review of biochemistry 2007

Peled et al.
Annual review of immunology 2008

Muramatsu et al.
Cell 2000

Stavnezer et al.
Annual review of immunology 2008

Journal of Experimental Medicine 2007

Journal of Biological Chemistry 2007

DNA REPAIR AMSTERDAM 2008

Kannouche et al.
Molecular cell 2004

PNAS 2005

Moldovan et al.
Cell 2007

Iyer et al.
Chemical Reviews 2006

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