Structural basis of pyrimidine-pyrimidone (6-4) photoproduct recognition by UV-DDB in the nucleosome.
Structural basis of pyrimidine-pyrimidone (6-4) photoproduct recognition by UV-DDB in the nucleosome.
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DOI：
10.1038/srep16330
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发表时间：
2015-11-17
影响因子：
4.6
通讯作者：
Kurumizaka H
中科院分区：
文献类型：
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作者：
Osakabe A;Tachiwana H;Kagawa W;Horikoshi N;Matsumoto S;Hasegawa M;Matsumoto N;Toga T;Yamamoto J;Hanaoka F;Thomä NH;Sugasawa K;Iwai S;Kurumizaka H
UV-DDB是核苷酸切除修复途径的起始因子，通过碱基翻转机制识别6-4PP损伤。由于基因组DNA几乎完全容纳在核小体中，如果损伤发生在核小体中，特别是在直接接触组蛋白表面的链上，那么6-4PP碱基的翻转应该是非常困难的。在这里，我们报告说，UV-DDB有效地结合到核小体6- 4PP旋转定位在溶剂可及或闭塞的表面上。我们测定了在这些旋转位置含有6- 4PP的核小体的晶体结构，发现6-4PP DNA区域是灵活无序的，特别是在暴露于溶剂的链中。6-4PP的这一特性可能有助于UV-DDB与受损核小体的结合。我们提出了第一个原子分辨率的图片的核小体内的相邻的嘧啶碱基的有害的DNA交联，并提供了在染色质中的UV-DDB损伤识别的机制框架。
UV-DDB, an initiation factor for the nucleotide excision repair pathway, recognizes 6–4PP lesions through a base flipping mechanism. As genomic DNA is almost entirely accommodated within nucleosomes, the flipping of the 6–4PP bases is supposed to be extremely difficult if the lesion occurs in a nucleosome, especially on the strand directly contacting the histone surface. Here we report that UV-DDB binds efficiently to nucleosomal 6–4PPs that are rotationally positioned on the solvent accessible or occluded surface. We determined the crystal structures of nucleosomes containing 6–4PPs in these rotational positions, and found that the 6–4PP DNA regions were flexibly disordered, especially in the strand exposed to the solvent. This characteristic of 6–4PP may facilitate UV-DDB binding to the damaged nucleosome. We present the first atomic-resolution pictures of the detrimental DNA cross-links of neighboring pyrimidine bases within the nucleosome, and provide the mechanistic framework for lesion recognition by UV-DDB in chromatin.