Regulation of DNA polymerase beta by the LMP1 oncoprotein of EBV through the nuclear factor-kappaB pathway

Cancer Res. 2009 Jun 15;69(12):5177-85. doi: 10.1158/0008-5472.CAN-08-2866. Epub 2009 Jun 2.


The repair DNA polymerase beta (Polbeta), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of Polbeta 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 Polbeta, 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 Polbeta decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-kappaB in the LMP1-mediated Polbeta 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 proximal kappaB binding site (-211 to -199nt) of the Polbeta promoter. This result was correlated with a specific Polbeta kappaB transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Polbeta overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-kappaB activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Transformed
  • DNA
  • DNA Polymerase beta / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation
  • Mice
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Viral Matrix Proteins / physiology*


  • EBV-associated membrane antigen, Epstein-Barr virus
  • NF-kappa B
  • Viral Matrix Proteins
  • DNA
  • DNA Polymerase beta

Associated data

  • RefSeq/NW_923907