Sarkar B
Research Institute of the Hospital for Sick Children, Toronto, Ontario, Canada.
Nutrition. 1995 Sep-Oct;11(5 Suppl):646-9.
Carcinogenesis induced by metals is well documented, but the mechanism of cancer induction is not clear. It is known that transition metals can damage DNA by free radicals generated by Fenton reaction. We are investigating a class of DNA-binding proteins, known as zinc finger proteins, which act as transcription factors binding specifically to short DNA-sequences and controlling the transcription of a number of genes. We have demonstrated the ability of metals such as cobalt, cadmium, copper, nickel, and iron to substitute for zinc in zinc finger protein. The results gave further insight on the structural contribution of metal toward DNA-binding and identified metal interactions that may be of relevance to metal-induced DNA damage and carcinogenesis. The key to the mechanism of metal-mediated carcinogenesis is the enhancement of cellular redox processing by metals. Cobalt and iron in the presence of H2O2 catalyze the degradation of deoxyribose and induce DNA damage. Thus, a redox metal substituted for zinc in the zinc finger protein is expected to generate free radicals to cause DNA damage. Consequently, such metals bound to a DNA-binding protein generating potentially harmful free radicals in close proximity to DNA may be of relevance to the toxicity and carcinogenicity of these metals.
金属诱导的致癌作用已有充分记录，但癌症诱导机制尚不清楚。已知过渡金属可通过芬顿反应产生的自由基破坏DNA。我们正在研究一类称为锌指蛋白的DNA结合蛋白，它们作为转录因子，特异性结合短DNA序列并控制许多基因的转录。我们已经证明钴、镉、铜、镍和铁等金属能够在锌指蛋白中替代锌。这些结果进一步深入了解了金属对DNA结合的结构贡献，并确定了可能与金属诱导的DNA损伤和致癌作用相关的金属相互作用。金属介导致癌作用机制的关键在于金属对细胞氧化还原过程的增强作用。钴和铁在过氧化氢存在下催化脱氧核糖降解并诱导DNA损伤。因此，预计在锌指蛋白中替代锌的氧化还原金属会产生自由基导致DNA损伤。因此，与DNA结合蛋白结合并在DNA附近产生潜在有害自由基的此类金属可能与这些金属的毒性和致癌性有关。
