College of Life Sciences, Peking University, Beijing 100871, China.
Genes Dev. 2011 Oct 1;25(19):2041-56. doi: 10.1101/gad.17010011.
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.
转录性 R 环是一种异常的 RNA:DNA 杂交体，已在从细菌到人类的生物体中检测到。这些结构已在真核生物中显示会导致 DNA 损伤和重排；然而，这些影响的机制在很大程度上仍然未知。为了研究这一点，我们首先表明 R 环的形成会诱导大肠杆菌中的染色体 DNA 重排和重组，就像在真核生物中一样。更重要的是，我们随后表明 R 环的形成会导致 DNA 复制叉停滞，而这实际上是 R 环对基因组稳定性影响的基础。引人注目的是，我们发现复制的衰减强烈抑制了大肠杆菌和 HeLa 细胞中 R 环介导的 DNA 重排。因此，我们的发现提供了直接证据表明 R 环的形成会损害 DNA 复制，这是 R 环对从细菌到人类的基因组稳定性产生有害影响的原因。
