This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-2866v1 69/12/5177    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Faumont, N. Articles by Meggetto, F. PubMed PubMed Citation Articles by Faumont, N. Articles by Meggetto, F.

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

¹ Institut National de la Sante et de la Recherche Medicale-U563, CPTP; ² Université Toulouse III Paul-Sabatier, Institut Claude de Préval, IFR30; and ³ Centre National de la Recherche Scientifique-UMR-5089, IPBS, groupe Instabilité Génétique et Cancer, Toulouse, France; ⁴ Centre National de la Recherche Scientifique-UMR-6101, CHU Dupuytren, Université de Limoges, Equipe labellisée La Ligue, Limoges, France; and ⁵ Centre National de la Recherche Scientifique-UMR-8527, IBL, BP-447, Lille, France

Requests for reprints: Fabienne Meggetto, CPTP, Institut National de la Sante et de la Recherche Medicale-U563, CHU-Purpan, BP-3028, 31024 Toulouse Cedex-3, France. Phone: 33-5-62-74-45-39; Fax: 33-5-62-74-45-58; E-mail: fabienne.meggetto{at}inserm.fr.

Key Words: EBV • LMP1 • Polβ • NF-B • lymphoma

The repair DNA polymerase β (Polβ), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of Polβ 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 Polβ, 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 Polβ decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-B (NF-B) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-B in the LMP1-mediated Polβ 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 B binding site (–211 to –199nt) of the Polβ promoter. This result was correlated with a specific Polβ B transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Polβ overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-B activation. [Cancer Res 2009;69(12):5177–85]