Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide
Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide
复制标题
DOI：
10.1038/s41467-019-13674-5
复制
发表时间：
2019-12-13
影响因子：
16.6
通讯作者：
Chen, Chun-Long
中科院分区：
文献类型：
--
作者：
Brison, Olivier;El-Hilali, Sami;Chen, Chun-Long
常见脆性位点（CFS）是在复制应激时易于断裂的染色体区域，已知其在肿瘤发生期间驱动染色体重排。大多数CFSs嵌套在大的表达基因中，这表明转录可以引起它们的不稳定性;然而，潜在的机制仍然难以捉摸。全基因组复制时序分析表明，压力诱导的延迟/复制不足是CFS的标志。对新生转录本、复制起点定位和叉方向性的广泛的全基因组分析表明，80%的CFSs巢在起始事件较差的大转录域中，由长行程叉复制。在S期后期长时间旅行的分叉解释了CFS复制功能，而序列依赖性分叉障碍或迎面转录复制冲突的形成则没有。我们进一步表明，在S期转录抑制，抑制转录复制的遭遇，并防止原点重置，不能挽救CFS的稳定性。总而言之，我们的研究结果表明，转录依赖性抑制的起始事件延迟复制的大基因体，使它们不稳定。
Common fragile sites (CFSs) are chromosome regions prone to breakage upon replication stress known to drive chromosome rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription could elicit their instability; however, the underlying mechanisms remain elusive. Genome-wide replication timing analyses here show that stress-induced delayed/under-replication is the hallmark of CFSs. Extensive genome-wide analyses of nascent transcripts, replication origin positioning and fork directionality reveal that 80% of CFSs nest in large transcribed domains poor in initiation events, replicated by long-travelling forks. Forks that travel long in late S phase explains CFS replication features, whereas formation of sequence-dependent fork barriers or head-on transcription-replication conflicts do not. We further show that transcription inhibition during S phase, which suppresses transcription-replication encounters and prevents origin resetting, could not rescue CFS stability. Altogether, our results show that transcription-dependent suppression of initiation events delays replication of large gene bodies, committing them to instability.