Analysis of uracil DNA glycosylase in human colorectal cancer

C. Dusseau, Graeme Ian Murray, T. J. O'Kelly, H. E. Krokan, R. A. Keenan, H. L. McLeod

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Abstract

Uracil DNA glycosylase (UDG) is responsible for the removal of uracil present in DNA after cytosine deamination or misincorporation during replication. Colorectal cancer is widely treated with 5-FU, which leads to thymidylate synthase inhibition; this accounts for increased dUTP intracellular pools and subsequent uracil incorporation into DNA. Uracil misincorporation has also been implicated in the link between folate deficiency and colorectal cancer risk. As there is no information on UDG in colorectal cancer, this study characterized UDG activity and protein expression in a panel of 20 colorectal tumors and 6 colorectal cell lines. UDG activity in colorectal tissue is widely variable and it is statistically higher in tumor tissue (P=0.013) compared to normal bowel. Tumor versus normal activity ratios ranged from 0.49 to 2.2 (median 1.13). Among the six colorectal cell lines tested, UDG activity varied from 40 to 68 units and was markedly (1.7-fold) higher than in tumor tissue (P<0.0001). In both colorectal tissues and cell lines, UDG was expressed as both 29 kDa and 35 kDa forms. Total protein expression varied 3.2-fold in cell lines; variability was also found between patients and between normal and tumoral tissue for the same patient. This study demonstrates UDG protein and functional activity in human colorectal tumors and cell lines. The high tumor:normal tissue ratio supports further interest in base excision repair, through UDG, as a potential source of fluoropyrimidine resistance in colorectal cancer.

Original languageEnglish
Pages (from-to)393-399
Number of pages6
JournalInternational Journal of Oncology
Volume18
Issue number2
Publication statusPublished - 2001

Keywords

  • uracil DNA glycosylase
  • colorectal cancer
  • 5-fluorouracil
  • MITOCHONDRIAL FORMS
  • OKAZAKI FRAGMENTS
  • THYMINELESS DEATH
  • CARCINOMA-CELLS
  • UNG GENE
  • 5-FLUOROURACIL
  • NUCLEAR
  • METHYLTRANSFERASE
  • EXPRESSION
  • MISINCORPORATION

Cite this

Dusseau, C., Murray, G. I., O'Kelly, T. J., Krokan, H. E., Keenan, R. A., & McLeod, H. L. (2001). Analysis of uracil DNA glycosylase in human colorectal cancer. International Journal of Oncology, 18(2), 393-399.