Loss of PPP2R2A Inhibits Homologous Recombination DNA Repair and Predicts Tumor Sensitivity to PARP Inhibition
Loss of PPP2R2A Inhibits Homologous Recombination DNA Repair and Predicts Tumor Sensitivity to PARP Inhibition
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DOI：
10.1158/0008-5472.can-12-1667
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发表时间：
2012-12-15
期刊：
影响因子：
11.2
通讯作者：
Sablina, Anna
中科院分区：
文献类型：
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作者：
Kalev, Peter;Simicek, Michal;Sablina, Anna
可逆磷酸化在DNA修复中起关键作用。在这里，我们报告了功能缺失筛选的结果，该筛选确定了PP2A异三聚丝氨酸/苏氨酸磷酸酶PPP2R2A、PPP2R2D、PPP2R5A和PPP2R3C在双链断裂（DSB）修复中的作用。特别是，我们发现含有ppp2r2a的复合物直接使ATM在S367、S1893和S1981位点去磷酸化，以调节其在DSB位点的保留。PPP2R2A衰减引发的ATM磷酸化增加显著上调了下游效应激酶CHK2的活性，导致G(1)至s期细胞周期阻滞和BRCA1和RAD51下调。在肿瘤细胞中，阻断PPP2R2A从而破坏了高保真同源重组修复途径，使细胞对PARP小分子抑制剂敏感。我们发现PPP2R2A在非小细胞肺癌中普遍下调，提示PPP2R2A状态可作为预测PARP抑制治疗效果的标志物。综上所述，我们的结果加深了对PP2A家族磷酸酶在DNA修复中的作用的理解，并建议PPP2R2A作为临床PARP抑制剂反应的标记物。癌症Res;72 (24);6414 - 24。(c) 2012年AACR。
Reversible phosphorylation plays a critical role in DNA repair. Here, we report the results of a loss-of-function screen that identifies the PP2A heterotrimeric serine/threonine phosphatases PPP2R2A, PPP2R2D, PPP2R5A, and PPP2R3C in double-strand break (DSB) repair. In particular, we found that PPP2R2A-containing complexes directly dephosphorylated ATM at S367, S1893, and S1981 to regulate its retention at DSB sites. Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2, resulting in G(1) to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51. In tumor cells, blocking PPP2R2A thereby impaired the high-fidelity homologous recombination repair pathway and sensitized cells to small-molecule inhibitors of PARP. We found that PPP2R2A was commonly downregulated in non-small cell lung carcinomas, suggesting that PPP2R2A status may serve as a marker to predict therapeutic efficacy to PARP inhibition. In summary, our results deepen understanding of the role of PP2A family phosphatases in DNA repair and suggest PPP2R2A as a marker for PARP inhibitor responses in clinic. Cancer Res; 72(24); 6414-24. (c) 2012 AACR.