The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair
The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair
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DOI：
10.1016/j.molcel.2004.08.007
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发表时间：
2004-08-27
期刊：
影响因子：
16
通讯作者：
Donehower, LA
中科院分区：
文献类型：
--
作者：
Lu, XB;Bocangel, D;Donehower, LA
野生型p53诱导的磷酸酶PPM 1D（或Wip 1）是一种丝氨酸/苏氨酸磷酸酶，在紫外线和电离辐射后由p53转录上调。PPM 1D是转化试验中的癌基因，在几种人类肿瘤类型中扩增或过表达。在这里，我们证明了PPM 1D与尿嘧啶DNA糖基化酶的核亚型UNG 2相互作用，并抑制碱基切除修复（BER）。抑制PPM 1D磷酸酶活性的点突变消除了BER抑制，表明PPM 1D的去磷酸化对BER抑制很重要。我们已经确定了UNG 2磷酸化位点在苏氨酸6和126，表现出增强的磷酸化后，紫外线照射。UV诱导的UNG 2磷酸化形式在介导尿嘧啶相关DNA切割中比非磷酸化形式更活跃。UNG 2在磷酸苏氨酸6处的PPM 1D去磷酸化与UNG 2活性降低相关。因此，PPM 1D可能通过使UNG 2去磷酸化以促进其在DNA修复完成后的失活来抑制BER。
The wild-type p53-induced phosphatase PPM1D (or Wip1) is a serine/threonine phosphatase that is transcriptionally upregulated by p53 following ultraviolet and ionizing radiation. PPM1D is an oncogene in transformation assays and is amplified or overexpressed in several human tumor types. Here, we demonstrate that PPM1D interacts with the nuclear isoform of uracil DNA glycosylase, UNG2, and suppresses base excision repair (BER). Point mutations that inactivate PPM1D phosphatase activity abrogate BER suppression, indicating that dephosphorylation by PPM1D is important for BER inhibition. We have identified UNG2 phosphorylation sites at threonines 6 and 126 that exhibit enhanced phosphorylation following UV irradiation. The UV-induced phosphorylated forms of UNG2 are more active than nonphosphorylated forms in mediating uracil-associated DNA cleavage. PPM1D dephosphorylation of UNG2 at phosphothreonine 6 is associated with reduced UNG2 activity. Thus, PPM1D may inhibit BER by dephosphorylating UNG2 to facilitate its inactivation after completion of DNA repair.