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Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells

Nature Immunology volume 8, pages 1132–1139 (2007)Cite this article

Abstract

Antigen-specific B cells are selected in germinal centers, the structure in which these cells proliferate while accomplishing genome-remodeling processes such as class-switch recombination and somatic hypermutation. These events are associated with considerable genotoxic stress, which cells tolerate through suppression of DNA-damage responses by Bcl-6, a transcription factor required for the formation of germinal centers. Here we show that the expression of Bcl-6 is regulated by DNA damage through a signaling pathway that promotes Bcl-6 degradation. After DNA damage accumulated, the kinase ATM promoted Bcl-6 phosphorylation, leading to its interaction with the isomerase Pin1 and its degradation by the ubiquitin-proteasome system. Because Bcl-6 is required for the maintenance of germinal centers, our findings suggest that the extent of genotoxic stress controls the fate of germinal center B cells by means of Bcl-6.

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Figure 1: DNA damage induces Bcl-6 downregulation in B cells.
Figure 2: DNA damage–induced phosphorylation of Bcl-6 and protein degradation.
Figure 3: Pin1 interacts with Bcl-6.
Figure 4: The interaction of Bcl-6 with Pin1 is enhanced after genotoxic insults and is required for DNA damage–induced degradation.
Figure 5: Increased germinal center formation in Pin1−/− mice immunized with sheep red blood cells.

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Acknowledgements

We thank P. Le, M. Uranishi, Q. Shen, P.M. Smith and T. Mo for technical support; I. Schieren for help in cell sorting; G. Cattoretti for pathology consultation in the analysis of Pin1−/− mice; A. Melnick and S. Ranuncolo for discussions; and R. Baer, L. Pasqualucci and D. Dominguez-Sola for discussions and critical reading of the manuscript. Supported by the National Institutes of Health (R.T.P. and R.D.-F.) and the Leukemia Lymphoma Society (Specialized Center of Research Grant).

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  1. Ryan T Phan

    Present address: Present address: CBR Institute for Biomedical Research, Children's Hospital, Harvard University Medical School, Boston, Massachusetts 02115, USA.,

Authors and Affiliations

  1. the Departments of Pathology and Genetics & Development, Institute for Cancer Genetics, and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, 10032, New York, USA

    Ryan T Phan, Masumichi Saito, Yukiko Kitagawa & Riccardo Dalla-Favera

  2. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Anthony R Means

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Contributions

R.T.P. and M.S. did the experiments in Figures 1,2,3,4,5 (R.T.P.) and Figures 2d and 3a,b (M.S.); Y.K. isolated centroblasts from tonsil biopsies; A.R.M. provided Pin1−/− mice; and R.D.-F. provided project planning and supervision.

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Correspondence to Riccardo Dalla-Favera.

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Phan, R., Saito, M., Kitagawa, Y. et al. Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells. Nat Immunol 8, 1132–1139 (2007). https://doi.org/10.1038/ni1508

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