Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
Miroculus, Inc., San Francisco, CA, USA.
Nat Struct Mol Biol. 2019 Jan;26(1):67-77. doi: 10.1038/s41594-018-0171-0. Epub 2018 Dec 31.
Although DNA replication is a fundamental aspect of biology, it is not known what determines where DNA replication starts and stops in the human genome. We directly identified and quantitatively compared sites of replication initiation and termination in untransformed human cells. We found that replication preferentially initiates at the transcription start site of genes occupied by high levels of RNA polymerase II, and terminates at their polyadenylation sites, thereby ensuring global co-directionality of transcription and replication, particularly at gene 5' ends. During replication stress, replication initiation is stimulated downstream of genes and termination is redistributed to gene bodies; this globally reorients replication relative to transcription around gene 3' ends. These data suggest that replication initiation and termination are coupled to transcription in human cells, and propose a model for the impact of replication stress on genome integrity.
尽管 DNA 复制是生物学的一个基本方面，但尚不清楚是什么决定了人类基因组中 DNA 复制的起点和终点。我们直接鉴定并定量比较了未转化的人类细胞中复制起始和终止的位点。我们发现，复制优先起始于被高水平 RNA 聚合酶 II 占据的基因的转录起始位点，并在其多聚腺苷酸化位点终止，从而确保了转录和复制的全局共方向性，特别是在基因的 5'端。在复制应激期间，复制起始被刺激在基因下游，终止重新分配到基因主体；这在基因 3'端周围使复制相对于转录整体重新定向。这些数据表明，在人类细胞中，复制起始和终止与转录相偶联，并提出了一个关于复制应激对基因组完整性影响的模型。
