Replication inhibitors modulate instability of an expanded trinucleotide repeat at the myotonic dystrophy type 1 disease locus in human cells.
Replication inhibitors modulate instability of an expanded trinucleotide repeat at the myotonic dystrophy type 1 disease locus in human cells.
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复制抑制剂调节人类细胞强直性肌营养不良 1 型疾病基因座处扩展的三核苷酸重复序列的不稳定性。
DOI：
10.1086/379523
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发表时间：
2003
影响因子：
9.8
通讯作者：
C. E. Pearson
中科院分区：
文献类型：
--
作者：
Zhi Yang;Rachel Lau;Julien L. Marcadier;D. Chitayat;C. E. Pearson
基因特异性CTG/CAG重复扩增与至少14种人类疾病相关，包括强直性肌营养不良1型（DM 1）。我们对三核苷酸不稳定性的大部分理解来自非人类模型，这些模型呈现出混合的结果，支持复制错误或独立于细胞分裂的过程作为原因。然而，在患者细胞中的疾病位点发生的机制知之甚少。使用来自患有DM 1的胎儿的原代成纤维细胞，我们已经表明患病（CTG）（216）等位基因的自发扩增发生在增殖细胞中，而不是在静止细胞中。扩增是“同步的”，突变频率接近100%。此外，用已知改变DNA合成但不直接损伤DNA的试剂处理细胞。用含羞草素抑制复制起始对不稳定性没有影响。用阿非迪霉素抑制前导链和滞后链的合成，或用emphidocin仅阻断滞后链的合成，显著增强了CTG扩增。令人惊讶的是，只有扩增的DM 1等位基因被改变，而正常等位基因（CTG）（12）和其他重复基因座不受影响。标准和小池聚合酶链反应显示，抑制剂将大多数细胞的短扩增幅度提高了三倍，而11%-25%的细胞经历了122-170个重复的增加，大小为（CTG）（338）-（CTG）（386）。在成年DM 1细胞系中观察到类似的结果。我们的研究结果支持的DM 1 CTG扩展患者成纤维细胞内的复制叉动力学扰动的作用。这是第一份报告，重复长度的变化，具体到一个疾病等位基因可以调制外源添加的化合物。
Gene-specific CTG/CAG repeat expansion is associated with at least 14 human diseases, including myotonic dystrophy type 1 (DM1). Most of our understanding of trinucleotide instability is from nonhuman models, which have presented mixed results, supporting replication errors or processes independent of cell division as causes. Nevertheless, the mechanism occurring at the disease loci in patient cells is poorly understood. Using primary fibroblasts derived from a fetus with DM1, we have shown that spontaneous expansion of the diseased (CTG)(216) allele occurred in proliferating cells but not in quiescent cells. Expansions were "synchronous," with mutation frequencies approaching 100%. Furthermore, cells were treated with agents known to alter DNA synthesis but not to directly damage DNA. Inhibiting replication initiation with mimosine had no effect upon instability. Inhibiting both leading- and lagging-strand synthesis with aphidicolin or blocking only lagging strand synthesis with emetine significantly enhanced CTG expansions. It was striking that only the expanded DM1 allele was altered, leaving the normal allele, (CTG)(12), and other repeat loci unaffected. Standard and small-pool polymerase chain reaction revealed that inhibitors enhanced the magnitude of short expansions in most cells threefold, whereas 11%-25% of cells experienced gains of 122-170 repeats, to sizes of (CTG)(338)-(CTG)(386). Similar results were observed for an adult DM1 cell line. Our results support a role for the perturbation of replication fork dynamics in DM1 CTG expansions within patient fibroblasts. This is the first report that repeat-length alterations specific to a disease allele can be modulated by exogenously added compounds.
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DNA合成抑制后S期中国仓鼠卵巢细胞中DNA的过度复制。
DOI：
--
发表时间：
1987
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hoy,CA;Rice,GC;Kovacs,M;Schimke,RT
通讯作者：
Schimke,RT
影响因子：
3.5
作者：
Khajavi, M;Tari, AM;Ashizawa, T
通讯作者：
Ashizawa, T
共刺激激动剂作为自身免疫性疾病的新型免疫疗法。
影响因子：
13.6
作者：
Sun,Yonglian;Subudhi,SumitK;Fu,Yang-Xin
通讯作者：
Fu,Yang-Xin
影响因子：
3.5
作者：
G. Wright;U. Hübscher;N. Khan;F. Focher;A. Verri
通讯作者：
G. Wright;U. Hübscher;N. Khan;F. Focher;A. Verri