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

Faumont, Nathalie; Clorennec, Christophe Le; Teira, Pierre; Goormachtigh, Gautier; Cottet, J; Canitrot, Yvan; Cazaux, Christophe; Hoffmann, Jean-Sébastien; Brousset, Pierre; Delsol, Georges; Feuillard, Jean

doi:10.1158/0008-5472.can-08-2866

Cited by 9 publications

(7 citation statements)

References 46 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with the fact that DNA-PK initiates canonical NHEJ processes rather than HR, we did not observe any contribution of Ku70 to NF-κB-mediated DSB repair. NF-κB was also proposed to transcriptionally induce polymerase β, which stimulates HR and causes genetic instabilities in tumour cells upon overexpression (32,33). Pathogenesis of Werner syndrome was also suggested to involve NF-κB signalling.…”

Section: Discussionmentioning

confidence: 99%

NF-κB regulates DNA double-strand break repair in conjunction with BRCA1–CtIP complexes

Volcic

Karl

Baumann

et al. 2011

Nucleic Acids Research

122

View full text Add to dashboard Cite

NF-κB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-κB can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-κB in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or cross-talk with p53. It was not mediated by the transcriptional NF-κB targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-κB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-κB interacts with CtIP–BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-κB activation indicating HR stimulation through DSB resection by the interacting CtIP–BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-κB-dependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-κB-mediated resistance to chemo- and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-κB activation.

show abstract

Section: Discussionmentioning

confidence: 99%

NF-κB regulates DNA double-strand break repair in conjunction with BRCA1–CtIP complexes

Volcic

Karl

Baumann

et al. 2011

Nucleic Acids Research

122

View full text Add to dashboard Cite

show abstract

“…Cytoplasmic extracts were prepared as described (30). Ultracentrifugation at 100,000 3 g for 1 h was performed to separate the cytosolic fraction (supernatant) from the organelles (pellet).…”

Section: Protein Extracts and Western Blottingmentioning

confidence: 99%

B7-H1, Which Represses EBV-Immortalized B Cell Killing by Autologous T and NK Cells, Is Oppositely Regulated by c-Myc and EBV Latency III Program at Both mRNA and Secretory Lysosome Levels

Durand-Panteix¹,

Farhat²,

Youlyouz-Marfak³

et al. 2012

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

EBV-immortalized B cells induce a complex immune response such that the virus persists as a clinically silent infection for the lifetime of the infected host. B7-H1, also called PD-L1, is a cosignaling molecule of the B7 family that can inhibit activated T cell effectors by interaction with its receptor PD-1. In this work, we have studied the dependence of B7-H1 on NF-κB and c-Myc, the two main transcription factors in EBV latency III proliferating B cells, on various lymphoblastoid and Burkitt lymphoma cell lines, some of them being inducible or not for the EBV latency III program and/or for c-Myc. We found that B7-H1 repressed killing of EBV-immortalized B cells by their autologous T and NK cells. At the mRNA level, NF-κB was a weak inducer whereas c-Myc was a strong repressor of B7-H1 expression, an effect mediated by STAT1 inhibition. At the protein level, B7-H1 molecules were stored in both degradative and unconventional secretory lysosomes. Surface membrane B7-H1 molecules were constitutively internalized and proteolyzed in lysosomes. The EBV latency III program increased the amounts of B7-H1–containing secretory lysosomes and their export to the surface membrane. By repressing actin polymerization, c-Myc blocked secretory lysosome migration and B7-H1 surface membrane export. In addition to B7-H1, various immunoregulatory molecules participating in the immunological synapse are stored in secretory lysosomes. By playing on actin polymerization, c-Myc could thus globally regulate the immunogenicity of transformed B cells, acting on export of secretory lysosomes to plasma membrane.

show abstract

“…We, and others, have observed elevated expression of Polβ in gastrointestinal tumors and cancers from the esophagus, colon and pancreas [9, 141–143]. In addition, chronic myelogenous leukemia (CML) [144] and infection by human papillomavirus 16 (HPV16) [145] or Epstein-Barr virus (EBV) [146] leads to elevated expression of Polβ. In many cases, mutations within the Polβ coding region results in over-expression of dysfunctional Polβ proteins [8].…”

Section: Dominant-negative Interference Of Polβ Function and The Impamentioning

confidence: 99%

Targeting DNA Polymerase ß for Therapeutic Intervention

Goellner

Svilar²,

Almeida³

et al. 2012

CMP

View full text Add to dashboard Cite

DNA damage plays a causal role in numerous disease processes. Hence, it is suggested that DNA repair proteins, which maintain the integrity of the nuclear and mitochondrial genomes, play a critical role in reducing the onset of multiple diseases, including cancer, diabetes and neurodegeneration. As the primary DNA polymerase involved in base excision repair, DNA polymerase β (Polβ) has been implicated in multiple cellular processes, including genome maintenance and telomere processing and is suggested to play a role in oncogenic transformation, cell viability following stress and the cellular response to radiation, chemotherapy and environmental genotoxicants. Therefore, Polβ inhibitors may prove to be effective in cancer treatment. However, Polβ has a complex and highly regulated role in DNA metabolism. This complicates the development of effective Polβ-specific inhibitors useful for improving chemotherapy and radiation response without impacting normal cellular function. With multiple enzymatic activities, numerous binding partners and complex modes of regulation from post-translational modifications, there are many opportunities for Polβ inhibition that have yet to be resolved. To shed light on the varying possibilities and approaches of targeting Polβ for potential therapeutic intervention, we summarize the reported small molecule inhibitors of Polβ and discuss the genetic, biochemical and chemical studies that implicate additional options for Polβ inhibition. Further, we offer suggestions on possible inhibitor combinatorial approaches and the potential for tumor specificity for Polβ-inhibitors.

show abstract

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

Cited by 9 publications

References 46 publications

NF-κB regulates DNA double-strand break repair in conjunction with BRCA1–CtIP complexes

NF-κB regulates DNA double-strand break repair in conjunction with BRCA1–CtIP complexes

B7-H1, Which Represses EBV-Immortalized B Cell Killing by Autologous T and NK Cells, Is Oppositely Regulated by c-Myc and EBV Latency III Program at Both mRNA and Secretory Lysosome Levels

Targeting DNA Polymerase ß for Therapeutic Intervention

Contact Info

Product

Resources

About