Dysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumours.
Dysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumours.
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DOI：
10.1038/s41389-021-00329-8
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发表时间：
2021-05-15
期刊：
影响因子：
6.2
通讯作者：
Gabrielli B
中科院分区：
文献类型：
--
作者：
Fernando M;Duijf PHG;Proctor M;Stevenson AJ;Ehmann A;Vora S;Skalamera D;Adams M;Gabrielli B
缺陷DNA修复被证明是癌症治疗中的有用靶点。目前，缺陷修复是通过特定的基因突变来识别的，然而缺陷修复是没有这些突变的癌症的共同特征。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。检查点信号传导成分的缺陷，如共济失调毛细血管扩张突变（ATM），发生在低比例的癌症中，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-PLK 1细胞周期检查点恢复途径，该途径负责退出G2期细胞周期检查点阻滞。我们证明，PP 6和AURKA的失调维持PLK 1激活升高，促进过早退出ATM，而不是ATR依赖的检查点阻滞。令人惊讶的是，负调节PLK 1的PP 2A的B55α亚基的缺失能够克服ATM和ATR检查点阻滞。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PP 6-AURKA-PLK 1-B55α检查点恢复途径的失调与缺陷性同源重组的特征和几种癌症类型中染色体不稳定性增加之间存在强相关性。这项工作已经确定了G2期DNA修复缺陷和染色体不稳定性的未实现来源，这些缺陷和不稳定性可能对针对缺陷修复的治疗敏感。
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.
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DOI：
10.1083/jcb.200510130
发表时间：
2006-04-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bekker-Jensen S;Lukas C;Kitagawa R;Melander F;Kastan MB;Bartek J;Lukas J
通讯作者：
Lukas J
DOI：
10.4161/cc.9.8.11470
发表时间：
2010-04-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Bower JJ;Zhou Y;Zhou T;Simpson DA;Arlander SJ;Paules RS;Cordeiro-Stone M;Kaufmann WK
通讯作者：
Kaufmann WK
影响因子：
56.9
作者：
Lee, JH;Paull, TT
通讯作者：
Paull, TT
DOI：
10.1073/pnas.1706392114
发表时间：
2017-07-18
影响因子：
11.1
作者：
Chen, Chun-Chin;Kass, Elizabeth M.;Jasin, Maria
通讯作者：
Jasin, Maria
影响因子：
64.8
作者：
Macurek, Libor;Lindqvist, Arne;Medema, Rene H.
通讯作者：
Medema, Rene H.