Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
SKI Stem Cell Research Facility, Sloan-Kettering Institute, New York, NY 10065, USA.
Mol Cell. 2014 Jan 9;53(1):19-31. doi: 10.1016/j.molcel.2013.10.029. Epub 2013 Nov 27.
Fragile X syndrome (FXS) is caused by a CGG repeat expansion in the FMR1 gene that appears to occur during oogenesis and during early embryogenesis. One model proposes that repeat instability depends on the replication fork direction through the repeats such that (CNG)n hairpin-like structures form, causing DNA polymerase to stall and slip. Examining DNA replication fork progression on single DNA molecules at the endogenous FMR1 locus revealed that replication forks stall at CGG repeats in human cells. Furthermore, replication profiles of FXS human embryonic stem cells (hESCs) compared to nonaffected hESCs showed that fork direction through the repeats is altered at the FMR1 locus in FXS hESCs, such that predominantly the CCG strand serves as the lagging-strand template. This is due to the absence of replication initiation that would typically occur upstream of FMR1, suggesting that altered replication origin usage combined with fork stalling promotes repeat instability during early embryonic development.
脆性 X 综合征 (FXS) 是由 FMR1 基因中的 CGG 重复扩展引起的，这种扩展似乎发生在卵子发生和早期胚胎发生过程中。一种模型提出，重复不稳定性取决于复制叉通过重复的方向，从而形成 (CNG)n 发夹样结构，导致 DNA 聚合酶停滞和滑动。在内源性 FMR1 基因座上对单个 DNA 分子上的 DNA 复制叉进展进行检查表明，复制叉在人类细胞中的 CGG 重复处停滞。此外，与非 FXS hESCs 相比，FXS hESCs 的复制谱表明，在 FXS hESCs 中，重复通过的复制叉方向在 FMR1 基因座上发生改变，使得 CCG 链主要作为滞后链模板。这是由于缺乏通常在上游发生的复制起始，这表明改变的复制起始用途与叉停滞相结合，促进了早期胚胎发育过程中的重复不稳定性。
