| Project/Area Number |
13214049
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyoto University |
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Principal Investigator |
OHMORI Haruo Kyoto University, Institute for Vnus Research, Associate professor, ウイルス研究所, 助教授 (10127061)
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| Project Period (FY) |
2001 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥46,500,000 (Direct Cost: ¥46,500,000)
Fiscal Year 2004: ¥11,500,000 (Direct Cost: ¥11,500,000)
Fiscal Year 2003: ¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2002: ¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2001: ¥11,300,000 (Direct Cost: ¥11,300,000)
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| Keywords | DNA damages / carcinogenesis / mutation / carcinogen / benzo[a]pyrene / DNA polymerase / estrogen / acetvllaminofluorenel / 当然変異 / 発ガン / 色素性乾皮症 / エストラジェン / グアニン / monoADPribose / DN損傷 / ノックアウトマウス / 蛋白質間相互作用 / 免疫細胞 / 体細胞超変異 / 肺がん / ES細胞 / バイパス合成 / Polκ / 発がん物質 / 遺伝子発現 |
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| Research Abstract |
Polk is one of the newly found DNA polymerases capable of bypassing DNA lesions. Polκ is structurally similar to Polη, which is encoded by the XPV gene responsible for Xeroderma Pigmentosum Variant, but it is supposed to have a lesion- specificity different from that of Polη. Unlike Polη, Polκ is unable to bypass UV-induced cyclobutane pyrimidine dimers (CPDs), but it is able to bypass dG-N2-BPDE adducts generated by the metabolites of benzo[a]pynere (B[a]P), which is believed to be an potent agent to induce lung cancers. The expression of Polκ was shown to be higher in cancerous cells of some lung cancer patients than in normal cells from the same patients.
We constructed mouse cell lines in which the Polκ gene coding for Polκ was disrupted, and found that Polκ-deficient cell is more sensitive to B[a]P treatment than the parental cell, generating an approximately 10-fold higher mutations. Furthermore, the spectrum of B[a]P-induced mutations in Polκ-deficient cell is different from that in the parental cell, which suggested that Polη might be responsible for most of B[a]P-induced mutations.
Metabolites of a female hormone, estrogen, are known to generate DNA lesions similar to dG-N2-BPDE. Polκ was found to bypass such estrogen-derived lesions accurately and efficiently. Acetylaminofluorene (AAF) generates adduct (dG-C8-AAF) at the C8 position of guanine in DNA as the major products, but it also generates adduct (dG-N2-AAF) at the N2 position of the same base. Polκ was found to bypass dG-N2-AAF efficiently by inserting the correct cytosine opposite the lesion. Thus, we conclude that Polκ is able to bypass dG-N2 adducts correctly in general.
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