Article abstract
Nature Immunology 8, 1132 - 1139 (2007)
Published online: 9 September 2007 | doi:10.1038/ni1508
Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells
Ryan T Phan1,3, Masumichi Saito1, Yukiko Kitagawa1, Anthony R Means2 & Riccardo Dalla-Favera1
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.
- Institute for Cancer Genetics, the Departments of Pathology and Genetics & Development, and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
- Present address: CBR Institute for Biomedical Research, Children's Hospital, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Correspondence to: Riccardo Dalla-Favera1 e-mail: rd10@columbia.edu
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