Transcription-dependent regulation of replication dynamics modulates genome stability
Transcription-dependent regulation of replication dynamics modulates genome stability
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DOI：
10.1038/s41594-018-0170-1
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发表时间：
2019-01-01
影响因子：
16.8
通讯作者：
Debatisse, Michelle
中科院分区：
文献类型：
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作者：
Blin, Marion;Le Tallec, Benoit;Debatisse, Michelle
常见脆性位点（CFS）是对复制应激高度敏感的基因座和癌症中染色体重排的热点。CFSs在S期后期复制，是细胞类型特异性的，并嵌套在大基因中。转录-复制冲突与低密度启动事件对脆弱性的相对影响目前正在辩论中。在这里，我们通过操纵鸡和人类细胞中内源性大基因的转录来解决转录、复制和不稳定性之间的关系。我们发现，用弱启动子诱导低转录会使大基因不稳定，而用强启动子刺激它们的转录会减轻不稳定性。值得注意的是，强启动子触发了向更早复制时间的转换，支持高转录水平使细胞在有丝分裂前有更多时间完成复制的模型。因此，转录可能有助于维持基因组的完整性，挑战了认为它完全是一种威胁的主流观点。
Common fragile sites (CFSs) are loci that are hypersensitive to replication stress and hotspots for chromosomal rearrangements in cancers. CFSs replicate late in S phase, are cell-type specific and nest in large genes. The relative impact of transcription-replication conflicts versus a low density in initiation events on fragility is currently debated. Here we addressed the relationships between transcription, replication, and instability by manipulating the transcription of endogenous large genes in chicken and human cells. We found that inducing low transcription with a weak promoter destabilized large genes, whereas stimulating their transcription with strong promoters alleviated instability. Notably, strong promoters triggered a switch to an earlier replication timing, supporting a model in which high transcription levels give cells more time to complete replication before mitosis. Transcription could therefore contribute to maintaining genome integrity, challenging the dominant view that it is exclusively a threat.