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首页> 外文期刊>Biochemistry >Binding to cisplatin-modified DNA by the saccharomyces cerevisiae HMGB protein Nhp6A
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Binding to cisplatin-modified DNA by the saccharomyces cerevisiae HMGB protein Nhp6A

机译：酿酒酵母HMGB蛋白Nhp6A与顺铂修饰的DNA结合

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Nhp6A is an aboundant non-histone chromatin-associated protein in Saccharomyces cerevisiae that contains a minor groove DNA binding motif called the HMG box.In this report,we show that Nhp6Ap binds to cisplatin intrastrand cross-links on duplex DNA with a 40-fold greater affinity than to unmodified DNA with the same sequence.Nevertheless.Nhp6Ap bound to cisplatinated DNA readily exchanges onto unmodified DNA.Phenanthroline-copper footprinting and two-dimensional NMR on complexes of wild-type and mutant Nhp6Ap with DNA were employed to probe the mode of binding to the cisplatin lesion.Recognition of the cisplatin adduct requires a surface-exposed phenylalanine on Nhp6Ap that promotes bending of DNA by inserting into the helix from the minor groove.We propose that Nhp6Ap targets the cisplatin adduct by means of intercalation by the phenylalanine and that it can bind in either orientation with respect to the DNA lesion.A methionine,which also insets between base paire and functions in target selection on numodified DNA,plays no apparent role in recognitioin of the cisplatin lesion.Basic amino acids within the N-terminal arm of Nhp6Ap are required for high-affinity binding to the cisplatin adduct as well as to numodified DNA.Cisplatin mediates its cytotoxicity by forming covalent adducts on DNA,and we find that triagle opennhp6a/b mutants are hypersensitive to cisparison with the wild-type strain.In contrast,triagle open nhp6a/b mutants are slightly more resistant to hydrogen peroxide and ultraviolet irradiation.Therefore,Nhp6A/Bp appears to directly or indirectly function in yeast to enhance cellular resistance to cisplatin.
机译：Nhp6A是酿酒酵母中一种丰富的非组蛋白染色质相关蛋白，其包含一个称为HMG框的小沟DNA结合基序。在本报告中，我们显示Nhp6Ap与双链DNA上的顺铂内链交联结合了40倍。然而，与顺铂DNA结合的Nhp6Ap可以很容易地交换到未修饰的DNA上。邻菲咯啉-铜印迹和二维NMR分别在野生型和突变型Nhp6Ap与DNA的复合物中进行探测。顺铂加合物的识别需要在Nhp6Ap上暴露于表面的苯丙氨酸，该苯丙氨酸通过从小沟插入螺旋线来促进DNA弯曲。我们建议Nhp6Ap通过苯丙氨酸的插入作用靶向顺铂加合物并且它可以相对于DNA损伤以任何方向结合。甲硫氨酸，它也插入碱基对和tar中的功能之间顺铂修饰后的顺铂损害的选择没有任何明显作用.Nhp6Ap N末端臂内的基本氨基酸是与顺铂加合物和顺铂修饰DNA高亲和力结合所必需的。顺铂介导其细胞毒性通过在DNA上形成共价加合物，我们发现triagle opennhp6a / b突变体对野生型菌株的顺式分化高度敏感。相比之下，triagle opennhp6a / b突变体对过氧化氢和紫外线的抵抗力稍强。因此，Nhp6A / Bp在酵母中似乎直接或间接起作用，以增强细胞对顺铂的耐药性。

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