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

F. Lemée, C. Bavoux, M. J. Pillaire, A. Bieth, C. R. Machado, S. D. Pena, R. Guimbaud, J. Selves, J. S. Hoffmann, C. Cazaux

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish
Pages (from-to)3387-3394
Number of pages8
JournalOncogene
Volume26
Issue number23
DOIs
StatePublished - 17 May 2007
Externally publishedYes

Keywords

  • Colorectal cancer
  • CRE
  • DNA polymerase kappa
  • Genetic instability
  • Promoter
  • SP1

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