Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes
Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes
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DOI：
10.1016/j.molcel.2011.10.013
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发表时间：
2011-12-23
期刊：
影响因子：
16
通讯作者：
Tora, Laszlo
中科院分区：
文献类型：
--
作者：
Helmrich, Anne;Ballarino, Monica;Tora, Laszlo
我们发现，转录大于800 kb的人类基因所需的时间跨越一个以上的完整细胞周期，而它们的转录速度等于较小的基因。独立于它们的表达状态，我们发现长基因复制较晚。在S期晚期伴随转录和复制的区域表现出被称为共同脆性位点（CFS）的DNA断裂热点。这种CFS不稳定性取决于潜在的长基因的表达。我们发现，RNA：DNA杂交（R环）形成在转录/复制碰撞的网站和RNase H1的功能，以抑制CFS的不稳定性。总之，我们的研究结果表明，在最长的人类基因上，转录机制与复制叉的碰撞是不可避免的，产生R环和随后的CFS形成。功能性复制机制需要参与解决转录和复制机制之间的冲突，以确保基因组的稳定性。
We show that the time required to transcribe human genes larger than 800 kb spans more than one complete cell cycle, while their transcription speed equals that of smaller genes. Independently of their expression status, we find the long genes to replicate late. Regions of concomitant transcription and replication in late S phase exhibit DNA break hot spots known as common fragile sites (CFSs). This CFS instability depends on the expression of the underlying long genes. We show that RNA:DNA hybrids (R-loops) form at sites of transcription/replication collisions and that RNase H1 functions to suppress CFS instability. In summary, our results show that, on the longest human genes, collisions of the transcription machinery with a replication fork are inevitable, creating R-loops and consequent CFS formation. Functional replication machinery needs to be involved in the resolution of conflicts between transcription and replication machineries to ensure genomic stability.