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首页> 外文期刊>Nucleic Acids Research >PARP1 suppresses homologous recombination events in mice in vivo
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PARP1 suppresses homologous recombination events in mice in vivo

机译：PARP1抑制小鼠体内的同源重组事件

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摘要

Recent studies suggest that PARP1 inhibitors, several of which are currently in clinical trial, may selectively kill BRCA1/2 mutant cancers cells. It is thought that the success of this therapy is based on immitigable lethal DNA damage in the cancer cells resultant from the concurrent loss or inhibition of two DNA damage repair pathways: single-strand break (SSB) repair and homologous recombination repair (HRR). Presumably, inhibition of PARP1 activity obstructs the repair of SSBs and during DNA replication, these lesions cause replication fork collapse and are transformed into substrates for HRR. In fact, several previous studies have indicated a hyper-recombinogenic phenotype in the absence of active PARP1 in vitro or in response to DNA damaging agents. In this study, we demonstrate an increased frequency of spontaneous HRR in vivo in the absence of PARP1 using the p(un) assay. Furthermore, we found that the HRR events that occur in Parp1 nullizygous mice are associated with a significant increase in large, clonal events, as opposed to the usually more frequent single cell events, suggesting an effect in replicating cells. In conclusion, our data demonstrates that PARP1 inhibits spontaneous HRR events, and supports the model of DNA replication transformation of SSBs into HRR substrates.
机译：最近的研究表明，PARP1抑制剂可能会选择性杀死BRCA1 / 2突变癌细胞，其中一些目前正在临床试验中。认为该疗法的成功是基于癌细胞中不可估量的致死性DNA损伤，该损伤是由两种DNA损伤修复途径（单链断裂（SSB）修复和同源重组修复（HRR））的同时丢失或抑制导致的。据推测，PARP1活性的抑制会阻碍SSB的修复，并且在DNA复制期间，这些损伤会导致复制叉塌陷并转化为HRR的底物。实际上，先前的一些研究表明，在体外没有活性PARP1或对DNA损伤剂无反应的情况下，会出现超重组表型。在这项研究中，我们证明了使用p（un）分析在缺乏PARP1的情况下体内自发性HRR的频率增加。此外，我们发现发生在Parp1 nullizygous小鼠中的HRR事件与大型克隆事件的显着增加相关，与通常更频繁的单细胞事件相反，这表明在复制细胞中有作用。总之，我们的数据表明PARP1抑制自发性HRR事件，并支持SSB到HRR底物的DNA复制转化模型。

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