The oncogenic phosphatase WIP1 negatively regulates nucleotide excision repair.
The oncogenic phosphatase WIP1 negatively regulates nucleotide excision repair.
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DOI：
10.1016/j.dnarep.2010.04.005
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发表时间：
2010-07-01
期刊：
影响因子：
3.8
通讯作者：
Donehower LA
中科院分区：
文献类型：
--
作者：
Nguyen TA;Slattery SD;Moon SH;Darlington YF;Lu X;Donehower LA
核苷酸切除修复（NER）是人类修复紫外线诱导的DNA损伤（如嘧啶（6-4）嘧啶酮光产物和环丁烷嘧啶二聚体（CPD））的唯一机制。响应于UV损伤，共济失调毛细血管扩张突变和Rad 3相关（ATR）激酶磷酸化并激活几种下游效应蛋白，如p53和XPA，以阻止细胞周期进展，刺激DNA修复或启动凋亡。然而，在DNA修复完成后，必须有活跃的机制将细胞恢复到预应力稳态。这种恢复的一个重要部分必须包括降低p53和NER活性以及从DNA损伤位点去除修复蛋白复合物的过程。由于损伤反应的激活部分通过磷酸化发生，因此磷酸酶是DNA损伤和修复反应的稳态调节剂的明显候选者。因此，我们研究了丝氨酸/苏氨酸野生型p53诱导的磷酸酶1（WIP 1/PPM 1D）是否可以调节NER。WIP 1过表达抑制NER和CPD修复的动力学，而WIP 1缺失增强NER动力学和CPD修复。这种NER抑制依赖于WIP 1磷酸酶活性，因为磷酸酶死亡的WIP 1突变体不能抑制NER。此外，WIP 1主要通过对NER的影响来抑制UV诱导的损伤修复的动力学，因为XPD缺陷细胞在修复UV损伤时不会被过表达的WIP 1进一步抑制。Wip 1基因敲除小鼠能快速修复CPD，并比野生型小鼠经历更少的UV诱导凋亡。体外磷酸酶测定将XPA和XPC鉴定为NER途径中的两个潜在WIP 1靶标。因此，WIP 1可以通过在UV诱导的DNA损伤修复后使XPA和XPC以及其他NER蛋白和调节剂去磷酸化和失活来抑制NER动力学。
Nucleotide excision repair (NER) is the only mechanism in humans to repair UV-induced DNA lesions such as pyrimidine (6–4) pyrimidone photoproducts and cyclobutane pyrimidine dimers (CPD). In response to UV damage, the ataxia telangiectasia mutated and Rad3-related (ATR) kinase phosphorylates and activates several downstream effector proteins, such as p53 and XPA, to arrest cell cycle progression, stimulate DNA repair, or initiate apoptosis. However, following the completion of DNA repair, there must be active mechanisms that restore the cell to a prestressed homeostatic state. An important part of this recovery must include a process to reduce p53 and NER activity as well as to remove repair protein complexes from the DNA damage sites. Since activation of the damage response occurs in part through phosphorylation, phosphatases are obvious candidates as homeostatic regulators of the DNA damage and repair responses. Therefore, we investigated whether the serine/threonine wild-type p53-induced phosphatase 1 (WIP1/PPM1D) might regulate NER. WIP1 overexpression inhibits the kinetics of NER and CPD repair, whereas WIP1 depletion enhances NER kinetics and CPD repair. This NER suppression is dependent on WIP1 phosphatase activity, as phosphatase-dead WIP1 mutants failed to inhibit NER. Moreover, WIP1 suppresses the kinetics of UV-induced damage repair largely through effects on NER, as XPD-deficient cells are not further suppressed in repairing UV damage by overexpressed WIP1. Wip1 null mice quickly repair their CPD and undergo less UV-induced apoptosis than their wild-type counterparts. In vitro phosphatase assays identify XPA and XPC as two potential WIP1 targets in the NER pathway. Thus WIP1 may suppress NER kinetics by dephosphorylating and inactivating XPA and XPC and other NER proteins and regulators after UV-induced DNA damage is repaired.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E
影响因子：
16
作者：
Lu, XB;Bocangel, D;Donehower, LA
通讯作者：
Donehower, LA
DOI：
10.1073/pnas.202485699
发表时间：
2002-10-01
影响因子：
11.1
作者：
Adimoolam, S;Ford, JM
通讯作者：
Ford, JM
影响因子：
30.8
作者：
Li, J;Yang, Y;Powers, S
通讯作者：
Powers, S