Defective DNA repair is being demonstrated to be a useful target in cancer treatment. Currently, defective repair is identified by specific gene mutations, however defective repair is a common feature of cancers without these mutations. DNA damage triggers cell cycle checkpoints that are responsible for co-ordinating cell cycle arrest and DNA repair. Defects in checkpoint signalling components such as ataxia telangiectasia mutated (ATM) occur in a low proportion of cancers and are responsible for reduced DNA repair and increased genomic instability. Here we have investigated the AURKA-PLK1 cell cycle checkpoint recovery pathway that is responsible for exit from the G2 phase cell cycle checkpoint arrest. We demonstrate that dysregulation of PP6 and AURKA maintained elevated PLK1 activation to promote premature exit from only ATM, and not ATR-dependent checkpoint arrest. Surprisingly, depletion of the B55α subunit of PP2A that negatively regulates PLK1 was capable of overcoming ATM and ATR checkpoint arrests. Dysregulation of the checkpoint recovery pathway reduced S/G2 phase DNA repair efficiency and increased genomic instability. We found a strong correlation between dysregulation of the PP6-AURKA-PLK1-B55α checkpoint recovery pathway with signatures of defective homologous recombination and increased chromosomal instability in several cancer types. This work has identified an unrealised source of G2 phase DNA repair defects and chromosomal instability that are likely to be sensitive to treatments targeting defective repair.

缺陷DNA修复已被证明是癌症治疗中的有用靶标。目前，缺陷修复是通过特定的基因突变来识别的，但是缺陷修复是没有这些突变的癌症的普遍特征。DNA损伤触发细胞周期检查点，负责协调细胞周期停滞和DNA修复。检查点信号成分中的缺陷，例如共济失调毛细血管扩张症（ATM）突变，在癌症中的比例很小，并导致DNA修复减少和基因组不稳定性增加。在这里，我们研究了AURKA-PLK1细胞周期检查点恢复途径，该途径负责退出G2期细胞周期检查点停滞。我们证明PP6和AURKA的失调维持了升高的PLK1激活以促进仅从ATM提早退出，而不是依赖ATR的检查站逮捕。出人意料的是，消极调节PLK1的PP2A的B55α亚基的消耗能够克服ATM和ATR检查点的逮捕。检查点恢复途径的失调降低了S / G2期DNA修复效率并增加了基因组不稳定性。我们发现PP6-AURKA-PLK1-B55α检查点恢复途径的失调与同源重组缺陷的标志和几种类型的染色体不稳定增加之间存在密切的相关性。这项工作已经确定了G2期DNA修复缺陷和染色体不稳定的未实现来源，这些缺陷可能对靶向缺陷修复的治疗敏感。消极调节PLK1的PP2A的B55α亚基的清除能够克服ATM和ATR检查点的逮捕。检查点恢复途径的失调降低了S / G2期DNA修复效率并增加了基因组不稳定性。我们发现PP6-AURKA-PLK1-B55α检查点恢复途径的失调与同源重组缺陷的标志和几种类型的染色体不稳定增加之间存在密切的相关性。这项工作已经确定了G2期DNA修复缺陷和染色体不稳定的未实现来源，这些缺陷可能对靶向缺陷修复的治疗敏感。消极调节PLK1的PP2A的B55α亚基的清除能够克服ATM和ATR检查点的逮捕。检查点恢复途径的失调降低了S / G2期DNA修复效率并增加了基因组不稳定性。我们发现PP6-AURKA-PLK1-B55α检查点恢复途径的失调与同源重组缺陷的标志和几种类型的染色体不稳定增加之间存在密切的相关性。这项工作已经确定了G2期DNA修复缺陷和染色体不稳定的未实现来源，这些缺陷可能对靶向缺陷修复的治疗敏感。我们发现PP6-AURKA-PLK1-B55α检查点恢复途径的失调与同源重组缺陷的标志和几种类型的染色体不稳定增加之间存在密切的相关性。这项工作已经确定了G2期DNA修复缺陷和染色体不稳定的未实现来源，这些缺陷可能对靶向缺陷修复的治疗敏感。我们发现PP6-AURKA-PLK1-B55α检查点恢复途径的失调与同源重组缺陷的标志和几种类型的染色体不稳定增加之间存在密切的相关性。这项工作已经确定了G2期DNA修复缺陷和染色体不稳定的未实现来源，这些缺陷可能对靶向缺陷修复的治疗敏感。