Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Dev Cell. 2015 Jul 6;34(1):85-95. doi: 10.1016/j.devcel.2015.04.019. Epub 2015 Jun 11.
Recent findings have identified highly transcribed genes as a source of genome instability; however, the degree to which large-scale shifts in transcriptional activity cause DNA damage was not known. One example of a large-scale shift in transcriptional activity occurs during development, when maternal regulators are destroyed and zygotic genome activation (ZGA) occurs. Here, we show that ZGA triggers widespread chromosome damage in the primordial germ cells of the nematode C. elegans. We show that ZGA-induced DNA damage activates a checkpoint response, the damage is repaired by factors required for inter-sister homologous recombination, and topoisomerase II plays a role in generating the damage. These findings identify ZGA as a source of intrinsic genome instability in the germline and suggest that genome destabilization may be a general consequence of extreme shifts in cellular transcriptional load.
最近的研究结果表明，转录活跃的基因是基因组不稳定的一个来源；然而，大规模转录活性变化导致 DNA 损伤的程度尚不清楚。转录活性的大规模变化的一个例子发生在发育过程中，此时母体调控因子被破坏，合子基因组激活（ZGA）发生。在这里，我们表明 ZGA 触发线虫 C. elegans 原始生殖细胞中的广泛染色体损伤。我们表明，ZGA 诱导的 DNA 损伤激活检查点反应，损伤由同源重组姐妹链所需的因子修复，拓扑异构酶 II 在产生损伤中起作用。这些发现确定了 ZGA 是生殖细胞中固有基因组不稳定性的一个来源，并表明基因组不稳定性可能是细胞转录负荷急剧变化的普遍后果。
