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首页> 外文期刊>Journal of Molecular Biology >DM2 CCTG*CAGG repeats are crossover hotspots that are more prone to expansions than the DM1 CTG*CAG repeats in Escherichia coli.
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DM2 CCTG*CAGG repeats are crossover hotspots that are more prone to expansions than the DM1 CTG*CAG repeats in Escherichia coli.

机译：DM2 CCTG * CAGG重复序列是交叉热点，比大肠杆菌中的DM1 CTG * CAG重复序列更易于扩展。

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摘要

Myotonic dystrophy type 2 (DM2) is caused by the extreme expansion of the repeating tetranucleotide CCTG*CAGG sequence from <30 repeats in normal individuals to approximately 11,000 for the full mutation in certain patients. This repeat is in intron 1 of the zinc finger protein 9 gene on chromosome 3q21. Since prior work demonstrated that CTG*CAG and GAA*TTC triplet repeats (responsible for DM1 and Friedreich's ataxia, respectively) can expand by genetic recombination, we investigated the capacity of the DM2 tetranucleotide repeats to also expand during this process. Both gene conversion and unequal crossing over are attractive mechanisms to effect these very large expansions. (CCTG*CAGG)n (where n=30, 75, 114 or 160) repeats showed high recombination crossover frequencies (up to 27-fold higher than the non-repeating control) in an intramolecular plasmid system in Escherichia coli. Furthermore, a distinct orientation effect was observed where orientation II (CAGG on the leading strand template) was more prone to recombine. Expansions of up to double the length of the tetranucleotide repeats were found. Also, the repeating tetranucleotide sequence was more prone to expansions (to give lengths longer than a single repeating tract) than deletions as observed for the CTG*CAG and GAA*TTC repeats. We determined that the DM2 tetranucleotide repeats showed a lower thermodynamic stability when compared to the DM1 trinucleotide repeats, which could make them better targets for DNA repair events, thus explaining their expansion-prone behavior. Genetic studies in SOS-repair mutants revealed high frequencies of recombination crossovers although the SOS-response itself was not induced. Thus, the genetic instabilities of the CCTG*CAGG repeats may be mediated by a recombination-repair mechanism that is influenced by DNA structure.
机译：2型强直性肌营养不良症（DM2）是由于重复的四核苷酸CCTG * CAGG序列从正常个体中的<30个重复序列的极端扩展到某些患者的完全突变而导致的大约11,000的极端扩展而引起的。该重复在染色体3q21上的锌指蛋白9基因的内含子1中。由于先前的工作表明CTG * CAG和GAA * TTC三联体重复序列（分别负责DM1和Friedreich共济失调）可以通过基因重组来扩展，因此我们研究了DM2四核苷酸重复序列在此过程中也可以扩展的能力。基因转换和不平等的交叉都是影响这些非常大的扩展的诱人机制。 （CCTG * CAGG）n（其中n = 30、75、114或160）重复序列在大肠杆菌的分子内质粒系统中显示出较高的重组交换频率（比非重复对照高27倍）。此外，观察到明显的取向效应，其中取向II（前导链模板上的CAGG）更易于重组。发现扩展到四核苷酸重复序列的长度的两倍。同样，与对CTG * CAG和GAA * TTC重复序列观察到的缺失相比，重复的四核苷酸序列更易于扩增（给出比单个重复序列更长的长度）。我们确定，与DM1三核苷酸重复序列相比，DM2四核苷酸重复序列显示出较低的热力学稳定性，这可能使其成为DNA修复事件的更好靶标，从而解释了其易于扩增的行为。 SOS修复突变体的遗传研究表明重组交叉的频率很高，尽管没有诱导出SOS响应本身。因此，CCTG * CAGG重复序列的遗传不稳定性可能是由受DNA结构影响的重组修复机制介导的。

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