Wells R D, Parniewski P, Pluciennik A, Bacolla A, Gellibolian R, Jaworski A
Institute of Biosciences and Technology, Center for Genome Research, Department of Biochemistry and Biophysics, Texas A & M University, Texas Medical Center, Houston, Texas 77030-3303, USA.
J Biol Chem. 1998 Jul 31;273(31):19532-41. doi: 10.1074/jbc.273.31.19532.
Genetic instability investigations on three triplet repeat sequences (TRS) involved in human hereditary neurological diseases (CTG.CAG, CGG.CCG, and GAA.TTC) revealed a high frequency of small expansions or deletions in 3-base pair registers in Escherichia coli. The presence of G to A polymorphisms in the CTG.CAG sequences served as reporters for the size and location of these instabilities. For the other two repeat sequences, length determinations confirmed the conclusions found for CTG.CAG. These studies were conducted in strains deficient in methyl-directed mismatch repair or nucleotide excision repair in order to investigate the involvement of these postreplicative processes in the genetic instabilities of these TRS. The observation that small and large instabilities for (CTG.CAG)175 fall into distinct size classes (1-8 repeats and approximate multiples of 41 repeats, respectively) leads to the conclusion that more than one DNA instability process is involved. The slippage of the complementary strands of the TRS is probably responsible for the small deletions and expansions in methyl-directed mismatch repair-deficient and nucleotide excision repair-deficient cells. A model is proposed to explain the observed instabilities via strand misalignment, incision, or excision, followed by DNA synthesis and ligation. This slippage-repair mechanism may be responsible for the small expansions in type 1 hereditary neurological diseases involving polyglutamine expansions. Furthermore, these observations may relate to the high frequency of small deletions versus a lower frequency of large instabilities observed in lymphoblastoid cells from myotonic dystrophy patients.
对参与人类遗传性神经疾病的三个三联体重复序列（TRS，即CTG.CAG、CGG.CCG和GAA.TTC）进行的基因不稳定性研究显示，在大肠杆菌中，3个碱基对的寄存器中存在高频的小片段扩增或缺失。CTG.CAG序列中G到A多态性的存在可作为这些不稳定性的大小和位置的报告分子。对于其他两个重复序列，长度测定证实了对CTG.CAG所得出的结论。这些研究是在甲基导向错配修复或核苷酸切除修复缺陷的菌株中进行的，以研究这些复制后过程在这些TRS基因不稳定性中的作用。（CTG.CAG）175的小不稳定性和大不稳定性分别属于不同的大小类别（分别为1 - 8个重复和大约41个重复的倍数）这一观察结果得出结论，即涉及不止一种DNA不稳定性过程。TRS互补链的滑动可能是甲基导向错配修复缺陷和核苷酸切除修复缺陷细胞中小片段缺失和扩增的原因。提出了一个模型，通过链错配、切割或切除，随后进行DNA合成和连接来解释观察到的不稳定性。这种滑动修复机制可能是导致涉及多聚谷氨酰胺扩增的1型遗传性神经疾病中小片段扩增的原因。此外，这些观察结果可能与强直性肌营养不良患者淋巴母细胞中观察到的小片段缺失高频出现以及大片段不稳定性低频出现有关。
