三核苷酸重复序列失稳定机制:重复序列形成non-B二级结构的必要性和细胞反式作用因子的作用(英文)

Mechanism of Trinucleotide Repeats Instabilities: The Necessities of Repeat Non-B Secondary Structure Formation and the Roles of Cellular Trans-acting Factors

与三核苷酸重复序列CAG·CTG、CGG·CCG和GAA·TTC扩增和缺失有关的分子机制尚不能得到清楚的阐释。体 外研究表明,上述疾病相关的重复序列可以在体外形成non-B二级结构,并介导重复序列扩增。然而,迄今为止,类似的 观察尚未在体内研究过程中得以实现。利用模型生物大肠杆菌和酵母等进行的有关研究并不能模拟三核苷酸重复序列的扩 增,这暗示三核苷酸重复序列的体内扩增可能与重复序列形成non-B二级结构关联性并不大。尽管理论上较长的三核苷 酸重复序列可以在复制和后复制过程中较易形成non-B DNA二级结构,但这样的二级结构倾向于导致重复序列出现“脆 性”,而不是扩增。事实上,患者所具有的三核苷酸重复序列扩增并非一定需要通过non-B二级结构的介导,这些重复序 列的扩增是可以通过一种RNA转录诱导的局部DNA重复序列的复制和其后的DNA重排得以发生。

The mechanism underlying CAG·CTC,CGG·CCG and GAA·TTC trinucleotide repeats expansion and contraction instabilities has not been clearly understood. Investigations in vitro have demonstrated that the disease causing repeats are capable of adopting non-B secondary structures that mediate repeats expansion. However, in vivo, similar observations have not been easily made so far. Investigations on the non-B secondary structure formation using E.coli, yeast etc cannot simulate the suggested repeats expansion instability. These could leave a space to infer a disassociation of the suggested repeats non-B secondary structure formation and the repeats expansion in vivo. Although longer trinucleotide repeats may be theoretically easier to form non-B DNA secondary structures in replication or in post-replication, however such non-B secondary structures are likely to cause repeat fragility rather than repeat expansion. In fact, repeat expansion as seen in patients may not necessarily require trinucleotide repeats to form non-B secondary structures, instead the repeat expansions can be produced through a RNA transcription-stimulated local repeat DNA replication and a subsequent DNA rearrangement.