B cells undergo DNA rearrangement to produce antibodies. In other cell types, DNA breaks can be lethal due to induction of apoptosis through a p53-mediated process. Phan and Dalla-Favera suggest that the transcriptional repressor protein BCL6, which is abundant in mature B cells of the germinal center (those undergoing somatic hypermutation and class switch recombination), represses p53 expression and allows the cells to tolerate low levels of genetic stress associated with DNA rearrangement. BCL6 repressed expression of a reporter gene containing the p53 promoter region, and BCL6 was detected associated with the p53 promoter in chromatin immunoprecipitation assays. When BCL6 expression was inhibited by siRNA, p53 mRNA increased to levels similar to those detected in naïve B cells that do not express BCL6. Furthermore, cells in which BCL6 was knocked down exhibited a larger increase in p53 abundance in response to genotoxic stress (etoposide treatment) compared with control cells. In wild-type cells, BCL6 is targeted for degradation by a ubiquitin-mediated proteasomal process in response to genotoxic stress. However, in cells expressing a mutant form of BCL6 that could not be ubiquitin tagged, apoptotic cell death was decreased and the induction of p53 expression and expression of p53 target genes were reduced compared to that observed in cells expressing wild-type BCL6. Constitutive expression of BCL6 through chromosomal translocation is associated with certain types of lymphoma, and it may be that repression of p53 is one mechanism by which these cancers arise.
R. T. Phan, R. Dalla-Favera, The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635-639 (2004). [Online Journal]