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Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination

Nature Immunology volume 10, pages 420–426 (2009)Cite this article

Abstract

Immunoglobulin class-switch recombination (CSR) requires activation-induced cytidine deaminase (AID). Deamination of DNA by AID in transcribed switch (S) regions leads to double-stranded breaks in DNA that serve as obligatory CSR intermediates. Here we demonstrate that the catalytic and regulatory subunits of protein kinase A (PKA) were specifically recruited to S regions to promote the localized phosphorylation of AID, which led to binding of replication protein A and subsequent propagation of the CSR cascade. Accordingly, inactivation of PKA resulted in considerable disruption of CSR because of decreased AID phosphorylation and recruitment of replication protein A to S regions. We propose that PKA nucleates the formation of active AID complexes specifically on S regions to generate the high density of DNA lesions required for CSR.

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Figure 1: Phosphorylation of AID by PKA modulates CSR.
Figure 2: Phosphorylation of AID is not required for interaction with S-region DNA.
Figure 3: Recruitment of PKA subunits to S regions during CSR.
Figure 4: PKA, AID and RPA form a macromolecular complex on S regions.
Figure 5: Conditional inactivation of PKA activity impairs CSR.
Figure 6: Induction of cAMP in activated splenic B cells.

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Acknowledgements

We thank T. Honjo (Kyoto University) for AID-deficient mice; J. Allison (Memorial Sloan-Kettering Cancer Center) for anti-CD3 and anti-CD28; P. Rothman (University of Iowa) for the plasmid pMIG-hPim1; and L. Denzin and D. Sant'Angelo, as well as members of their laboratories and members of the Chaudhuri laboratory, for discussions and technical assistance. Supported by the US National Institutes of Health (T32CA09149 to B.V.), the Damon Runyon Cancer Research Foundation (J.C.), the Bressler Scholars Foundation (J.C.), the Frederick Adler Chair for Junior Faculty (J.C.) and the Sloan-Kettering Institute (J.C.).

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Authors and Affiliations

  1. Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Bao Q Vuong, Mieun Lee, Shaheen Kabir, Cristina Irimia, Stephania Macchiarulo & Jayanta Chaudhuri

  2. Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, New York, New York, USA

    Cristina Irimia & Jayanta Chaudhuri

  3. Department of Pharmacology, University of Washington, Seattle, Washington, USA

    G Stanley McKnight

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Correspondence to Jayanta Chaudhuri.

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Vuong, B., Lee, M., Kabir, S. et al. Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination. Nat Immunol 10, 420–426 (2009). https://doi.org/10.1038/ni.1708

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