Overexpressed BCL6 (LAZ3) oncoprotein triggers apoptosis, delays S phase progression and associates with replication foci

One of the most frequent genetic abnormalities associated with non Hodgkin lymphoma is the structural alteration of the 5' non coding/regulatory regio n of the BCL6 (LAZ3) protooncogene. BCL6 encodes a POZ/Zn finger protein, a structure similar to that of many Drosophila developmental regulators and to another protein involved in a human hematopoietic malignancy, PLZF, BCL6 is a sequence specific transcriptional repressor controlling germinal cent er formation and T cell dependent immune response. Although the expression of BCL6 negatively correlates with cellular proliferation in different cell types, the influence of BCL6 on cell growth and survival is currently unkn own so that the way its deregulation may contribute to cancer remains elusi ve. To directly address this issue, we used a tetracycline-regulated system in human U2OS osteosarcoma cells and thus found that BCL6 mediates growth suppression associated with impaired S phase progression and apoptosis, Int erestingly, overexpressed BCL6 can colocalize with sites of ongoing DNA syn thesis, suggesting that it may directly interfere with S phase initiation a nd/or progression, In contrast, the isolated Zn finger region of BCL6, whic h binds BCL6 target sequence but lacks transcriptional repression activity, slows, but does not suppress, U2OS cell growth, is less efficient at delay ing S phase progression, and does not trigger apoptosis, Thus, for a large part, the effects of BCL6 overexpression on cell growth and survival depend on its ability to engage protein/protein interactions with itself and/or i ts transcriptional corepressors. That BCL6 restricts cell growth suggests t hat its deregulation upon structural alterations may alleviate negative con trols on the cell cycle and cell survival.