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首页> 外文期刊>Biochemistry >Exocyclic DNA Lesions Stimulate DNA Cleavage Mediated by Human Topoisomerase Ilalpha in Vitro and in Cultured Cells
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Exocyclic DNA Lesions Stimulate DNA Cleavage Mediated by Human Topoisomerase Ilalpha in Vitro and in Cultured Cells

机译：环外DNA损伤刺激体外和培养细胞中人类拓扑异构酶Ilalpha介导的DNA切割。

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摘要

DNA adducts are mutagenic and clastogenic.Because of their harmful nature,lesions are recognized by many proteins involved in DNA repair.However,mounting evidence suggests that lesions also are recognized by proteins with no obvious role in repair processes.One such protein is topoisomerase II,an essential enzyme that removes knots and tangles from the DNA.Because topoisomerase II generates a protein-linked double-stranded DNA break during its catalytic cycle,it has the potential to fragment the genome.Previous studies indicate that abasic sites and other lesions that distort the double helix stimulate topoisomerase II-mediated DNA cleavage.Therefore,to further explore interactions between DNA lesions and the enzyme,the effects of exocyclic adducts on DNA cleavage mediated by human topoisomerase IIalpha were determined.When located within the four-base overhang of a topoisomerase II cleavage site(at the +2 or +3 position 3' relative to the scissile bond),3,N~4-ethenodeoxycytidine,3,N~4-etheno-2'-ribocytidine,l,N~2-ethenodeoxyguanosine,pyrimido[l,2-alpha]purin-10(3H)-one deoxyribose(M_1dG),and 1,N~2-propanodeoxyguanosine increased DNA scission ~5-17-fold.Enhanced cleavage did not result from an increased affinity of topoisomerase IIalpha for adducted DNA or a decreased rate of religation.Therefore,it is concluded that these exocyclic lesions act by accelerating the forward rate of enzyme-mediated DNA scission.Finally,treatment of cultured human cells with 2-chloroacetaldehyde,a reactive metabolite of vinyl chloride that generates etheno adducts,increased cellular levels of DNA cleavage by topoisomerase IIalpha.This finding suggests that type II topoisomerases interact with exocyclic DNA lesions in physiological systems.
机译：DNA加合物具有致突变性和致突变性。由于其有害性质，许多DNA修复相关的蛋白质都能识别出病变。然而，越来越多的证据表明，病变也被蛋白质识别，在修复过程中没有明显作用。拓扑异构酶II ，是一种从DNA上消除结和缠结的必需酶。由于拓扑异构酶II在其催化周期内产生蛋白质连接的双链DNA断裂，因此有可能使基因组片段化。以前的研究表明，无碱基位点和其他病灶扭曲双螺旋刺激拓扑异构酶II介导的DNA裂解。因此，为进一步探讨DNA损伤与酶之间的相互作用，确定了环外加合物对人类拓扑异构酶IIalpha介导的DNA裂解的影响。拓扑异构酶II切割位点（相对于易断裂键3'的+2或+3位置），3，N〜4-乙氧基脱氧胞苷，3，N〜4 -etheno-2'-核糖胞苷，1，N〜2-乙氧基鸟苷，嘧啶[1,2-α嘌呤-10（3H）-一个脱氧核糖（M_1dG）和1，N〜2-丙氧基鸟苷增加了DNA断裂〜5 -17倍。增强的切割不是由于拓扑异构酶IIalpha对加成的DNA的亲和力增加或连接率降低而导致的。因此，可以得出结论，这些外环性损伤是通过促进酶介导的DNA分裂的正向速率来起作用的。 ，用2-氯乙醛（一种可产生乙炔加成物的氯乙烯的反应性代谢物）处理培养的人类细胞，增加了拓扑异构酶IIα对细胞的DNA裂解水平。这一发现表明II型拓扑异构酶与生理系统中的环外DNA损伤相互作用。

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