Expansion of trinucleotide repeats is associated with a growing number of human diseases. The mechanism and timing of expansion of the repeat tract are poorly understood. In humans, trinucleotide repeats show extreme meiotic instability, and expansion of the repeat tract has been suggested to occur in the germ-line mitotic divisions or postmeiotically during early divisions of the embryo. Studies in model organisms have indicated that polymerase slippage plays a major role in the repeat tract instability and meiotic instability is severalfold higher than the mitotic instability. We show here that meiotic instability of the CAG/CTG repeat tract in yeast is associated with double-strand break (DSB) formation within the repeated sequences, and that the DSB formation is dependent on the meiotic recombination machinery. The DSB repair results in both expansions and contractions of the CAG repeat tract.

译文

三核苷酸重复序列的扩增与越来越多的人类疾病有关。重复管道扩展的机理和时机知之甚少。在人类中,三核苷酸重复序列显示出极度的减数分裂不稳定,并且已暗示在胚系有丝分裂分裂中或在胚胎的早期分裂发生于减数分裂后,重复序列的扩增会发生。在模型生物中的研究表明,聚合酶滑移在重复道不稳定性中起主要作用,减数分裂不稳定性比有丝分裂不稳定性高出几倍。我们在这里显示,CAG / CTG重复序列在酵母中的减数分裂不稳定与重复序列内的双链断裂(DSB)形成有关,并且DSB的形成取决于减数分裂重组机制。 DSB修复导致CAG重复道的扩张和收缩。

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