BCL6-mediated Attenuation of DNA Damage Sensing Triggers Growth Arrest and Senescence through a p53-dependent Pathway in a Cell Context-dependent Manner

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.

Functional interaction of HTLV-1 Tax protein with the POZ domain of the transcriptional repressor BCL6

“…Inhibition of apoptosis and cell-cycle arrest in such cells is related to the ability of BCL6 to repress the expression of DNA damage sensing proteins such as p53 (Phan and Dalla-Favera, 2004) and ATR (Ranuncolo et al, 2007) and the cyclin-dependent kinase inhibitor p21 (Phan et al, 2005). Conversely, BCL6 induces apoptosis in CV-1 and HeLa cells (Yamochi et al, 1999), osteosarcoma cells (Albagli et al, 1999), NIH3T3 cells (Zhang et al, 2001) and normal fibroblasts (Ranuncolo et al, 2008). We show that Tax 1 increased the level of apoptosis and necrosis in an osteosarcoma cell line that expresses BCL6 in a tetracycline-regulated system (Albagli et al, 1999).…”

The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL

“…Indeed, ectopic expression of BCL6 in naive B cells or fibroblasts induces p53 responses and senescence. 40 Lymphoma cells are biologically different from primary B cells. Whether disruption of BCL6 functions contributes to these differences between normal and malignant B cells is unknown.…”

A kinase shRNA screen links LATS2 and the pRB tumor suppressor

“…2A, with the complete lists of shRNA targets in B). As expected, several of the shRNAs that scored in this screen target kinases that are known to regulate senescence pathways, including PAK6, RAF1, or IRAK (Courtois-Cox et al 2006;Ranuncolo et al 2008;Orjalo et al 2009). In addition, some of the shRNAs that enhanced the SA-b-gal activity had targets that have been shown to be up-regulated in tumors or cancer cell lines, including HIPK1 (up-regulated in breast cancer) (Kondo et al 2003), MAP2K5 (increased expression associated with metastatic prostate cancer) (Mehta et al 2003) and RAGE (activated in cancer and it promotes chronic inflammation, a favorable microenvironment for tumor formation) (Gebhardt et al 2008).…”