Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

The repair DNA polymerase beta (Pol beta), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of Pol beta has been reported in many tumor types that exhibit genetic aberrations, including EBV-related B-cell lymphomas. However, the mechanisms responsible for its overexpression have never been examined. Here, we report that both expression and activity of Pol beta, in EBV-immortalized B cells, are induced by several natural genetic variants of LMP1, an oncoprotein associated with the vast majority of EBV-related tumors. Conversely, we found that the expression of Pol beta decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-kappa B (NF-kappa B) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-kappa B in the LMP1-mediated Pol beta regulation. Using electrophoretic mobility shift assay experiments from several EBV-immortalized B-cell nuclear extracts, we identified an LMP1-dependent p50/c-Rel heterodimer on a Proxima kappa B binding site (-211 to -199nt) of the Pol beta promoter. This result was correlated with a specific Pol beta kappa B transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Pol beta overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-kappa B activation. [Cancer Res 2009; 69(12):5177-85]