R-loop-mediated genomic instability is caused by impairment of replication fork progression
R-loop-mediated genomic instability is caused by impairment of replication fork progression
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DOI：
10.1101/gad.17010011
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发表时间：
2011-10-01
影响因子：
10.5
通讯作者：
Li, Xialu
中科院分区：
文献类型：
--
作者：
Gan, Wenjian;Guan, Zhishuang;Li, Xialu
转录R环是一种异常的RNA：从细菌到人类的生物体中都发现了DNA杂交体。这些结构已经在真核生物中被证明可以导致DNA损伤和重排；然而，这些影响的机制在很大程度上仍然不清楚。为了研究这一点，我们首先证明了R环的形成在大肠杆菌中诱导了染色体DNA重排和重组，就像在真核生物中一样。更重要的是，我们证明了R环的形成导致DNA复制分叉停滞，这实际上是R环对基因组稳定性的影响的基础。引人注目的是，我们发现复制的减弱强烈地抑制了R环介导的DNA重排，在大肠杆菌和HeLa细胞中都是如此。因此，我们的发现提供了一个直接的证据，即R环的形成损害了DNA复制，这是R环对从细菌到人类的基因组稳定性的有害影响的原因。
Transcriptional R loops are anomalous RNA: DNA hybrids that have been detected in organisms from bacteria to humans. These structures have been shown in eukaryotes to result in DNA damage and rearrangements; however, the mechanisms underlying these effects have remained largely unknown. To investigate this, we first show that R-loop formation induces chromosomal DNA rearrangements and recombination in Escherichia coli, just as it does in eukaryotes. More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. Strikingly, we found that attenuation of replication strongly suppresses R-loop-mediated DNA rearrangements in both E. coli and HeLa cells. Our findings thus provide a direct demonstration that R-loop formation impairs DNA replication and that this is responsible for the deleterious effects of R loops on genome stability from bacteria to humans.