Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells
Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells
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DOI：
10.1038/ng870
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发表时间：
2002-05-01
期刊：
影响因子：
30.8
通讯作者：
Pearson, CE
中科院分区：
文献类型：
--
作者：
Cleary, JD;Nichol, K;Pearson, CE
疾病相关的三核苷酸重复序列不稳定性的机制涉及重复序列附近的顺式作用因子（顺式元件），但这些元件的性质尚不清楚。一个顺式元素可能是相对于重复的复制起源的位置。我们使用SV40 DNA复制系统研究了复制起始位置对灵长类细胞（CTG）(n)和（CAG）(n)稳定性的影响。根据SV40复制起点和重复链之间的距离，具有79个重复的模板主要产生扩增或缺失，或者保持完整。所有重复17次的模板都是稳定的。因此，影响相对于重复序列的冈崎片段起始位点的顺式元件是不稳定性的关键决定因素。该模型系统概括了在许多与三核苷酸重复相关的疾病中观察到的扩展偏差。我们的研究结果可以解释在不同染色体背景下观察到的CTG/CAG不稳定性的变化量。
The mechanism of disease-associated trinucleotide repeat instability involves cis-acting factors (cis-elements) in the vicinity of the repeat, but the nature of these elements is unknown. One cis-element may be the location of the replication origin relative to the repeat. We have used an SV40 DNA replication system to investigate the effect of the location of replication initiation on (CTG)(n).(CAG)(n) stability in primate cells. Depending on the distance between the SV40 replication origin and the repeat tract, templates with 79 repeats yield predominantly expansions or predominantly deletions or remain intact. All templates with 17 repeats are stable. Thus, cis-elements that affect the sites of Okazaki fragment initiation relative to the repeat are crucial determinants of instability. This model system recapitulates the bias for expansions observed in many of the diseases associated with trinucleotide repeats. Our results might explain the variable amounts of CTG/CAG instability that are observed in different chromosomal contexts.