Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation
Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation
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DOI：
10.1083/jcb.201404157
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发表时间：
2014-09-01
影响因子：
7.8
通讯作者：
Schildkraut, Carl L.
中科院分区：
文献类型：
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作者：
Gerhardt, Jeannine;Zaninovic, Nikica;Schildkraut, Carl L.
脆性 X 综合征 (FXS) 是由 CGG 重复扩增导致 FMR7 沉默引起的。具有前突变等位基因的女性有可能生下患有 FXS 的完全突变儿童。为了研究重复扩展的机制，我们检查了与单倍群 D 中的重复扩展相关的单核苷酸多态性 (SNP) 变体与位于重复上游 53 kb 附近的复制起点之间的关系。 FXS 人类胚胎干细胞 (hESC) 中不存在该起源，该细胞具有 SNP 变体 C，但存在于未受影响的 hESC 中，该细胞具有 T 变体。 SNP 直接映射到复制起点内。有趣的是，前突变 hESC 具有与未受影响的 bESC 类似的复制起点和 T 变体。这些结果表明，位于复制起点的 TIC SNP 可能导致 FXS hESC 中该复制起点的失活，从而导致通过重复的复制叉进程发生改变，这可能导致重复扩展至 FXS 完全突变。
Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR7 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a single-nucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located similar to 53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected bESCs. These results suggest that a TIC SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.