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

氧化应激诱导的序列特异性DNA损伤在癌症的发生和衰老中起着关键作用。因此，对其序列特异性的研究将为我们提供DNA损伤的生物学意义和癌症预防方面的有益发现。(1)氧化应激引起的序列特异性DNA损伤。我们用~(32)&gt；32&gt；P-5‘端标记的DNA，研究了致癌性苯并[α]芘代谢物BP-7，8-二醇-9，10-环氧化物对DNA损伤的序列特异性。BP-7，8-二酮强烈损伤与P53基因273密码子互补的5‘-ACG-3’序列的G和C。我们认为，DNA氧化损伤，尤其是双碱基损伤，除了参与DNA加合物的形成外，还可能参与BP致癌性的表达。此外，我们还证明，除了DNA加合物的形成外，DNA氧化损伤可能参与了多芳胺的致癌过程。此外，单芳胺、偶氮化合物、硝基co…更多的重量、有机溶剂、饮食因素以及医疗和医药产品也通过产生H_2O_2来诱导序列特异性DNA损伤。(2)氧化应激在衰老中的作用。我们证明了氧化应激(H_2O_2，NO+O_2^-，UVA)特异地氧化端粒序列中5‘-GGG-3’的鸟嘌呤生成8-oxodG。经UVA照射后的成纤维细胞，其末端限制性片段(TRF)随照射剂量的增加而减少。结论：氧化应激引起的端粒序列特异性损伤可能参与了端粒缩短率的增加，从而加速了衰老。(3)化学防腐剂的安全性评价。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损伤而致癌。另一方面，植酸不会对DNA造成损伤，可以作为潜在的癌症化学预防药物。较少

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