GCN5-deficiency remarkably enhances the sensitivity of B cells in response to 4-nitroquinoline 1-oxide

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  • Kikuchi Hidehiko
    Laboratory of Biological Chemistry, Department of Food and Nutrition, Shokei University Junior College Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo
  • Kuribayashi Futoshi
    Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo Department of Biochemistry, Kawasaki Medical School
  • Mimuro Hitomi
    Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo
  • Imajoh-Ohmi Shinobu
    Laboratory Center for Proteomics Research, Graduate School of Frontier Sciences, The Institute of Medical Science, The University of Tokyo

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A typical DNA-damaging agent 4-nitroquinoline 1-oxide (4NQO) is known as an experimental oral carcinogen. Although 4NQO was initially characterized as a UV-mimetic agent, it shows more complex effects inducing production of various covalent adducts, oxidative damage and DNA single strand break in DNA. To understand roles of histone acetyltransferase GCN5, which protects cells against UV-irradiation, on repair of 4NQO-induced DNA damage, we studied the sensitivity of chicken homozygous DT40 mutants, ∆GCN5, against 4NQO. After 4NQO treatment, the viability of ∆GCN5 was appreciably reduced (to ~25% at 6 hr) as compared to that of wild type DT40. Semiquantitative RT-PCR showed that transcription of DNA polymerase η (POLH) gene whose deficiency is responsible for a variant form of xeroderma pigmentosum was drastically down-regulated in ∆GCN5 (to ~25%). However, overexpression of POLH could not rescue ∆GCN5 from the enhanced sensitivity to 4NQO, unlike UV-irradiation. Our data suggested that GCN5 participates in control of the sensitivity against 4NQO, and the molecular mechanisms of GCN5-mediated repair of the 4NQO-induced DNA lesions are highly complex.

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