Unfolding of higher DNA structures formed by the d(CGG) triplet repeat by UP1 protein
Unfolding of higher DNA structures formed by the d(CGG) triplet repeat by UP1 protein
复制标题
DOI：
10.1111/j.1365-2443.2005.00896.x
复制
发表时间：
2005-10-01
期刊：
影响因子：
2.1
通讯作者：
Nakagama, H
中科院分区：
文献类型：
--
作者：
Fukuda, H;Katahira, M;Nakagama, H
脆性X综合征是由FMR 1基因第一外显子5 '非翻译区d（CGG）三联体重复扩增引起的，导致该基因沉默。据报道，d（CGG）重复序列在体外形成发夹和四链体结构，这些更高结构的形成可能是其在综合征中不稳定扩增的原因，尽管重复扩增的分子机制仍然难以捉摸。我们以前已经证明，UP1是hnRNP A1的蛋白水解产物，它使d（GGCAG）（5）和d（TTAGGG）（4）的分子内四链体结构展开，并消除了d（GGG）（n）位点对DNA合成的阻滞。在这里，我们证明了d（CGG）重复序列形成了一种特殊的DNA结构，它偏离了典型的B型结构。此外，通过CD光谱分析证明，UP1展开d（CGG）重复的这种特征性高级结构，并消除该位点对DNA合成的抑制。UP1的这种能力表明，DNA合成过程需要三联体重复序列的不寻常DNA结构的解折叠。
Fragile X syndrome is caused by expansion of a d(CGG) triplet repeat in the 5'-untranslated region of the first exon of the FMR1 gene resulting in silencing of the gene. The d(CGG) repeat has been reported to form hairpin and quadruplex structures in vitro, and formation of these higher structures could be responsible for its unstable expansion in the syndrome, although molecular mechanisms underlying the repeat expansion still remain elusive. We have previously proved that UP1, a proteolytic product of hnRNP A1, unfolds the intramolecular quadruplex structures of d(GGCAG)(5) and d(TTAGGG)(4) and abrogates the arrest of DNA synthesis at d(GGG)(n) sites. Here, we demonstrate that the d(CGG) repeat forms a peculiar DNA structure, which deviates from the canonical B-form structure. In addition, UP1 was demonstrated by CD spectrum analysis to unfold this characteristic higher structure of the d(CGG) repeat and to abrogate the arrest of DNA synthesis at the site. This ability of UP1 suggests that unfolding of unusual DNA structures of a triplet repeat is required for DNA synthesis processes.