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Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase κ in colorectal cancer

Oncogene volume 26, pages 3387–3394 (2007)Cite this article

Abstract

The low-fidelity DNA polymerases thought to be specialized in DNA damage processing are frequently misregulated in cancers. We show here that DNA polymerase kappa (polκ), prone to replicate across oxidative and aromatic adducts and known to function in nucleotide excision repair (NER), is downregulated in colorectal tumour biopsies. Contrary to the replicative polδ and polα, for which only activating domains were described, we identified an upstream 465-bp-long repressor region in the promoter of POLK. We also found an activating 237-bp region that includes stimulating protein-1 (SP1) and cyclic AMP-responsive element (CRE)-binding sites. Mutations at one CRE-binding site led to a dramatic 80% decrease in promoter activity. Alterations of the SP1-binding site also affected, to a lesser extent, the transcription. Gel shift assays confirmed the role played by CRE/SP1 recognition sequences. Moreover, ectopic expression of SP1 or CRE-binding protein (CREB) protein favoured polκ transcription. Finally, we found that polκ downexpression in colorectal biopsies correlated with a decreased level of CREB and SP1 transcripts. This work shows that the promoter of POLK is cis-controlled and suggests that silencing of CREB and SP1 proteins could contribute to downregulation of this repair polymerase in colorectal tumours.

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Acknowledgements

We thank K Gordien (Canceropole GSO) for annotation of tumours. This work was supported by the Ligue Nationale Contre le Cancer (labellization to JSH), Canceropole GSO (ACI 2004–2007 to CC) and CAPES-COFECUB (351/01). FL and CB were supported by the Institut National du Cancer (INCa) and LNCC/Association pour la Recherche sur le Cancer (ARC) fellowships, respectively.

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Author notes

  1. F Lemée and C Bavoux: Both these authors contributed equally to this work.

  2. J S Hoffmann and C Cazaux: Both these authors shared senior leadership.

Authors and Affiliations

  1. Laboratory Genetic Instability and Cancer, Institute of Pharmacology and Structural Biology, UMR CNRS 5089, Paul Sabatier University, Toulouse, France

    F Lemée, C Bavoux, M J Pillaire, A Bieth, J S Hoffmann & C Cazaux

  2. Department of Biochemistry and Immunology, Minas Gerais Federal University, MG, Brazil

    C R Machado & S D Pena

  3. Federation of Digestive Cancerology and Department of Anatomo-pathology, INSERM U563, Centre of Physiopathology of Toulouse-Purpan, Paul Sabatier University, Toulouse, France

    R Guimbaud & J Selves

Authors
  1. F Lemée
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  2. C Bavoux
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  9. J S Hoffmann
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  10. C Cazaux
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Corresponding author

Correspondence to C Cazaux.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lemée, F., Bavoux, C., Pillaire, M. et al. Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase κ in colorectal cancer. Oncogene 26, 3387–3394 (2007). https://doi.org/10.1038/sj.onc.1210116

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