ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice.
ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice.
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DOI：
10.1093/nar/gkp666
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发表时间：
2009-10
影响因子：
14.9
通讯作者：
Usdin K
中科院分区：
文献类型：
--
作者：
Entezam A;Usdin K
串联重复序列的扩张是重复扩张性疾病的原因，这是一组由20多种人类遗传疾病组成的疾病，其中包括脆性X(FX)综合征，这些疾病是由FMR1基因的重复扩张引起的。我们以前已经证明，ATM和Rad3相关(ATR)检查点激酶在FX前突变小鼠模型中保护基因组免受一种类型的重复扩张的影响。通过将FX预突变小鼠与共济失调毛细血管扩张突变(ATM)突变小鼠杂交，我们在这里表明ATM也可以防止重复扩张。然而，我们的数据表明，ATM敏感的机制与ATR敏感的机制不同。具体地说，当预突变等位基因通过父系传递并且无论后代的ATM基因型如何，在男性后代中发生扩张的频率更高时，ATM缺陷的影响就会更加明显。性别效应与发生在早期胚胎中的修复事件最一致，这种修复事件在女性中更有效，可能是X连锁DNA修复基因作用的结果。因此，我们的数据支持这一假设，即存在两种不同的FX重复扩增机制，一种是母体传播的ATR敏感机制，另一种是显示男性扩张偏见的ATM敏感机制。
Expansion of a tandem repeat tract is responsible for the Repeat Expansion diseases, a group of more than 20 human genetic disorders that includes those like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase protects the genome against one type of repeat expansion in a FX premutation mouse model. By crossing the FX premutation mice to Ataxia Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents repeat expansion. However, our data suggest that the ATM-sensitive mechanism is different from the ATR-sensitive one. Specifically, the effect of the ATM deficiency is more marked when the premutation allele is paternally transmitted and expansions occur more frequently in male offspring regardless of the Atm genotype of the offspring. The gender effect is most consistent with a repair event occurring in the early embryo that is more efficient in females, perhaps as a result of the action of an X-linked DNA repair gene. Our data thus support the hypothesis that two different mechanisms of FX repeat expansion exist, an ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive mechanism that shows a male expansion bias.
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