PARP inhibition during alkylation-induced genotoxic stress signals a cell cycle checkpoint response mediated by ATM.
PARP inhibition during alkylation-induced genotoxic stress signals a cell cycle checkpoint response mediated by ATM.
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DOI：
10.1016/j.dnarep.2009.07.010
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发表时间：
2009-11-02
期刊：
影响因子：
3.8
通讯作者：
Wilson SH
中科院分区：
文献类型：
--
作者：
Carrozza MJ;Stefanick DF;Horton JK;Kedar PS;Wilson SH
在检测到DNA损伤后，通过限制细胞周期进程，检查点对细胞生存和基因组稳定至关重要。甲基化损伤，当结合抑制PARP活性时，导致细胞周期依赖于ATR的S期延迟。在这里，我们证明了另一种检查点激酶ATM也参与了亚致死浓度的MMS与PARP抑制剂4-AN联合处理后的DNA损伤反应。ATM和PARP活性对于调节细胞对MMS的敏感性都很重要。ATM活性的丧失或其下游效应器Chk2的丧失限制了S相延迟的持续时间。MMS和4-AN联合作用可引起ATM和Chk2的磷酸化，其磷酸化的时程与S时相延迟有关。在没有ATM活性的情况下，Chk2的磷酸化水平降低。在没有ATM的情况下，Chk2的磷酸化似乎依赖于ATR和DNA-PK。结果表明，在启动碱基切除修复和抑制PARP活性之后，ATM的激活对于阻止细胞通过S期和保护MMS诱导的细胞毒性至关重要。
By limiting cell cycle progression following detection of DNA damage, checkpoints are critical for cell survival and genome stability. Methylated DNA damage, when combined with inhibition of PARP activity, results in an ATR-dependent S phase delay of the cell cycle. Here, we demonstrate that another checkpoint kinase, ATM, also is involved in the DNA damage response following treatment with a sub-lethal concentration of MMS combined with the PARP inhibitor 4-AN. Both ATM and PARP activity are important for moderating cellular sensitivity to MMS. Loss of ATM activity, or that of its downstream effector Chk2, limited the duration of the S phase delay. The combination of MMS and 4-AN resulted in ATM and Chk2 phosphorylation and the time course of phosphorylation for both kinases correlated with the S phase delay. Chk2 phosphorylation was reduced in the absence of ATM activity. The Chk2 phosphorylation that remained in the absence of ATM appeared to be dependent on ATR and DNA-PK. The results demonstrate that, following initiation of base excision repair and inhibition of PARP activity, ATM activation is critical for preventing the cell from progressing through S phase, and for protection against MMS-induced cytotoxicity.
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影响因子：
--
作者：
Aguilar-Quesada R;Muñoz-Gámez JA;Martín-Oliva D;Peralta A;Valenzuela MT;Matínez-Romero R;Quiles-Pérez R;Menissier-de Murcia J;de Murcia G;Ruiz de Almodóvar M;Oliver FJ
通讯作者：
Oliver FJ
影响因子：
7.3
作者：
Arienti, KL;Brunmark, A;Breitenbucher, JG
通讯作者：
Breitenbucher, JG
影响因子：
3.5
作者：
Bolderson, E;Scorah, J;Meuth, M
通讯作者：
Meuth, M
影响因子：
21.3
作者：
Jazayeri, A;Falck, J;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
4.8
作者：
Lavrik, OI;Prasad, R;Wilson, SH
通讯作者：
Wilson, SH