Disease-associated CAG·CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion.
Disease-associated CAG·CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion.
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DOI：
10.1093/nar/gku285
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发表时间：
2014-06
影响因子：
14.9
通讯作者：
Monckton DG
中科院分区：
文献类型：
--
作者：
Gomes-Pereira M;Hilley JD;Morales F;Adam B;James HE;Monckton DG
遗传上不稳定的扩增CAG·CTG三核苷酸重复序列是许多人类疾病的病因，包括亨廷顿病和1型强直性肌营养不良。人们仍然普遍认为，DNA聚合酶在复制过程中的滑动在扩增的积累中起着重要作用。然而，体细胞嵌合现象与组织的增殖能力和细胞周转率相关性很差，这表明在没有复制的情况下可以发生扩增。我们监测了通过化学或遗传操作细胞周期而停滞的转基因小鼠细胞中CAG·CTG重复序列的不稳定性，并为非分裂细胞中重复扩增的持续积累提供了明确的证据。重要的是，非分裂细胞的扩增速率至少与增殖细胞的扩增速率一样高。这些数据是一致的，在体内产生体细胞嵌合的细胞分裂独立的扩增的主要作用。虽然扩展可以在非分裂细胞中累积，但我们也表明细胞周期停滞不足以驱动不稳定性，这意味着其他因素是组织特异性不稳定性的关键调节因子。我们的数据表明，从头扩增事件不仅限于S期，并进一步支持细胞分裂独立的突变途径。
Genetically unstable expanded CAG·CTG trinucleotide repeats are causal in a number of human disorders, including Huntington disease and myotonic dystrophy type 1. It is still widely assumed that DNA polymerase slippage during replication plays an important role in the accumulation of expansions. Nevertheless, somatic mosaicism correlates poorly with the proliferative capacity of the tissue and rates of cell turnover, suggesting that expansions can occur in the absence of replication. We monitored CAG·CTG repeat instability in transgenic mouse cells arrested by chemical or genetic manipulation of the cell cycle and generated unequivocal evidence for the continuous accumulation of repeat expansions in non-dividing cells. Importantly, the rates of expansion in non-dividing cells were at least as high as those of proliferating cells. These data are consistent with a major role for cell division-independent expansion in generating somatic mosaicism in vivo. Although expansions can accrue in non-dividing cells, we also show that cell cycle arrest is not sufficient to drive instability, implicating other factors as the key regulators of tissue-specific instability. Our data reveal that de novo expansion events are not limited to S-phase and further support a cell division-independent mutational pathway.
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影响因子：
64.8
作者：
Kovtun, Irina V.;Liu, Yuan;McMurray, Cynthia T.
通讯作者：
McMurray, Cynthia T.
影响因子：
4.7
作者：
Lee, YJ;Park, SJ;Lee, SH
通讯作者：
Lee, SH
影响因子：
8.8
作者：
Kantartzis, Athena;Williams, Gregory M.;Bambara, Robert A.
通讯作者：
Bambara, Robert A.
DOI：
10.1073/pnas.1105461108
发表时间：
2011-10-18
影响因子：
11.1
作者：
Lang, Walter H.;Coats, Julie E.;McMurray, Cynthia T.
通讯作者：
McMurray, Cynthia T.
影响因子：
3.5
作者：
Kennedy, L;Evans, E;Shelbourne, PF
通讯作者：
Shelbourne, PF