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Analysis of sequence-specific DNA damage by oxidative stress and prevention of cancer and aging

分析氧化应激造成的序列特异性 DNA 损伤以及预防癌症和衰老

基本信息

批准号：
12470084
负责人：
KAWANISHI Shosuke
金额：
$ 8.9万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Sequence-specific DNA damage induced by oxidative stress plays the key role in carcinogenesis and aging. Therefore, study on its sequence specificity would provide us biological significance of DNA damage and beneficial findings for cancer prevention.(1)Role of sequence-specific DNA damage by oxidative stress in carcinogenesis.We investigated sequence specificity of DNA damage induced by BP-7,8-diol-9,10-epoxide, a carcinogenic benzo[α]pyrene metabolite, using ^<32>P-5'-end-labeled DNA. BP-7,8-dione strongly damaged G and C of the 5'-ACG-3' sequence complementary to codon 273(a hot spot) of the p53 gene. We concluded that oxidative DNA damage, especially double base lesions, may participate in the expression of carcinogenicity of BP in addition to DNA adduct formation. Furthermore, we demonstrated that in addition to DNA adduct formation, oxidative DNA damage may be involved in the carcinogenic process of polyaromatic amines. In addition, the monoaromatic amine, azo compounds, nitro co … More mpounds, organic solvents, dietary factors and medical and pharmaceutical products also induced sequence-specific DNA damage via H_2O_2 generation. We demonstrated that UVA radiation caused DNA oxidation at GG sequences in the presence of photosensitizers(folic acid, xanthone, etc).(2) Role of sequence-specific DNA damage by oxidative stress in aging.We demonstrated that oxidative stress (H_2O_2, NO+O_2^-, UVA) specifically oxidizes guanine of 5'-GGG-3' in telomere sequence to produce 8-oxodG. The terminal restriction fragment (TRF) from WI-38 fibroblasts irradiated with UVA decreased with increasing the irradiation doses. It is concluded that the site-specific damage in telomere sequence induced by oxidative stress may participate in an increase of telomere shortening rate, leading to acceleration of aging.(3) Safety evaluation of chemopreventive agents.We found that antioxidants (quercetin, isothiocyanates, curcumin, etc) can serve as prooxidants, capable of causing carcinogenesis via oxidative DNA damage. On the other hand, phytic acid does not cause DNA damage and can be potential cancer chemopreventive agent. Less

氧化应激诱导的序列特异性DNA损伤在致癌和衰老过程中起着关键作用。因此，研究其序列特异性将为我们提供DNA损伤的生物学意义，并为癌症预防提供有益的发现。(1)氧化应激引起的序列特异性DNA损伤在癌变中的作用。我们使用^<32>P-5'端标记的DNA，研究了致癌苯并[α]芘代谢物bp -7,8-二醇-9,10-环氧化物诱导的DNA损伤的序列特异性。bp -7,8-二酮强烈破坏了p53基因密码子273（热点）互补的5‘-ACG-3’序列中的G和C。我们认为DNA氧化损伤，尤其是双碱基损伤，除了DNA加合物的形成外，还可能参与BP致癌性的表达。此外，我们证明除了DNA加合物的形成，氧化DNA损伤可能参与多芳胺的致癌过程。此外，单芳胺、偶氮化合物、硝基化合物、有机溶剂、膳食因素和医药产品也可通过H_2O_2产生序列特异性DNA损伤。我们证明了UVA辐射在存在光敏剂（叶酸，山酮等）的情况下引起GG序列的DNA氧化。(2)氧化应激引起的序列特异性DNA损伤在衰老中的作用。我们证明氧化应激（H_2O_2, NO+O_2^-， UVA）特异性氧化端粒序列5‘- ggg -3’的鸟嘌呤产生8-oxodG。UVA辐照后WI-38成纤维细胞的末端限制性片段（TRF）随辐照剂量的增加而减少。由此可见，氧化应激诱导的端粒序列位点特异性损伤可能参与了端粒缩短速率的增加，从而导致衰老的加速。(3)化学预防剂的安全性评价。我们发现抗氧化剂（槲皮素，异硫氰酸酯，姜黄素等）可以作为促氧化剂，能够通过氧化DNA损伤引起致癌。另一方面，植酸不会造成DNA损伤，可能是潜在的癌症化学预防剂。少