TitleBCL6-mediated attenuation of DNA damage sensing triggers growth arrest and senescence through a p53-dependent pathway in a cell context-dependent manner.
Publication TypeJournal Article
Year of Publication2008
AuthorsRanuncolo, Stella Maris, Wang Ling, Polo Jose M., Dell'Oso Tania, Dierov Jamil, Gaymes Terry J., Rassool Feyruz, Carroll Martin, and Melnick Ari
JournalJ Biol Chem
Date Published2008 Aug 15
KeywordsCell Line, Chromatin, DNA, DNA Damage, Gamma Rays, Humans, Palatine Tonsil, Phosphorylation, Proto-Oncogene Proteins c-bcl-6, Tonsillectomy, Tumor Suppressor Protein p53

<p>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.</p>

Alternate JournalJ Biol Chem
PubMed ID18524763
PubMed Central IDPMC2504889
Grant ListR01 CA104348 / CA / NCI NIH HHS / United States
R01 CA100885 / CA / NCI NIH HHS / United States