Journal of Biological Chemistry
Volume 283, Issue 33, 15 August 2008, Pages 22565-22572
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Molecular Basis of Cell and Developmental Biology
BCL6-mediated Attenuation of DNA Damage Sensing Triggers Growth Arrest and Senescence through a p53-dependent Pathway in a Cell Context-dependent Manner*

https://doi.org/10.1074/jbc.M803490200Get rights and content
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The BCL6 oncogenic transcriptional repressor is required for development of germinal center centroblasts, which undergo simultaneous genetic recombination and massive clonal expansion. Although BCL6 is required for survival of centroblasts, its expression in earlier B-cells is toxic. Understanding these opposing effects could provide critical insight into normal B-cell biology and lymphomagenesis. We examined the transcriptional and biological effects of BCL6 in various primary cells. BCL6 repression of ATR was previously shown to play a critical role in the centroblast phenotype. Likewise, we found that BCL6 could impose an ATR-dependent phenotype of attenuated DNA damage sensing and repair in primary fibroblasts and B-cells. BCL6 induced true genomic instability because DNA repair was delayed and was qualitatively impaired, which could be critical for BCL6-induced lymphomagenesis. Although BCL6 can directly repress TP53 in centroblasts, BCL6 induced TP53 expression in primary fibroblasts and B-cells, and these cells underwent p53-dependent growth arrest and senescence in the presence of physiological levels of BCL6. This differential ability to trigger a functional p53 response explains at least in part the different biological response to BCL6 expression in centroblasts versus other cells. The data suggest that targeted re-activation of TP53 could be of therapeutic value in centroblast-derived lymphomas.

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*

This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA100885 (to M. C.) and R01 CA104348 (to A. M.) from NCI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Table S1.

1

Supported by a Cancer Research Institute fellowship.

2

Supported by the National Cancer Center.

3

Leukemia and Lymphoma Society Scholar in Clinical Research.