BCL6-mediated attenuation of DNA damage sensing triggers growth arrest and senescence through a p53-dependent pathway in a cell context-dependent manner Academic Article uri icon

Overview

MeSH Major

  • DNA Damage
  • Proto-Oncogene Proteins c-bcl-6
  • Tumor Suppressor Protein p53

abstract

  • 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.

publication date

  • August 15, 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2504889

Digital Object Identifier (DOI)

  • 10.1074/jbc.M803490200

PubMed ID

  • 18524763

Additional Document Info

start page

  • 22565

end page

  • 72

volume

  • 283

number

  • 33