Dang Tuyen T, Morales Julio C
Department of Neurosurgery, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
Department of Neurosurgery, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
Cancers (Basel). 2020 Jul 7;12(7):1821. doi: 10.3390/cancers12071821.
It was recently shown that the 5' to 3' exoribonuclease XRN2 is involved in the DNA damage response. Importantly, loss of XRN2 abrogates DNA double stranded break repair via the non-homologous end-joining pathway. However, the mechanistic details of how XRN2 functions in the non-homologous end-joining repair process are unknown. In this study, we elucidated that XRN2-mediated RNA:DNA hybrid resolution is required to allow Ku70 binding to DNA ends. These data suggest that XRN2 is required for the initiation of non-homologous end-joining repair. Interestingly, we uncovered a role for XRN2 in the homologous recombination repair pathway. Loss of XRN2 lead to a decrease in the repair of double strand breaks by homologous recombination. Strikingly, when we removed RNA:DNA hybrids by RNaseH1 over-expression, homologous recombination was not restored. We found RNA:DNA hybrid formation at and downstream of the DSB site, suggesting that unregulated transcription inhibits homologous recombination repair. In summary, our results indicate a relation between RNA:DNA hybrid resolution and double strand break repair pathway choice.
最近的研究表明，5'至3'外切核糖核酸酶XRN2参与DNA损伤反应。重要的是，XRN2的缺失会通过非同源末端连接途径消除DNA双链断裂修复。然而，XRN2在非同源末端连接修复过程中发挥作用的机制细节尚不清楚。在本研究中，我们阐明了XRN2介导的RNA:DNA杂交体解离是Ku70结合到DNA末端所必需的。这些数据表明XRN2是启动非同源末端连接修复所必需的。有趣的是，我们发现XRN2在同源重组修复途径中也发挥作用。XRN2的缺失导致同源重组对双链断裂的修复减少。引人注目的是，当我们通过过表达RNaseH1去除RNA:DNA杂交体时，同源重组并未恢复。我们发现在双链断裂位点及其下游形成了RNA:DNA杂交体，这表明不受调控的转录会抑制同源重组修复。总之，我们的结果表明RNA:DNA杂交体解离与双链断裂修复途径选择之间存在关联。
