Oliva-Trastoy M, Berthonaud V, Chevalier A, Ducrot C, Marsolier-Kergoat M-C, Mann C, Leteurtre F
Service de Biochimie et de Génétique Moléculaire, CEA/Saclay, Gif-sur-Yvette, France.
Oncogene. 2007 Mar 1;26(10):1449-58. doi: 10.1038/sj.onc.1209927. Epub 2006 Aug 28.
We previously demonstrated that type 2C protein phosphatases (PP2C) Ptc2 and Ptc3 are required for DNA checkpoint inactivation after DNA double-strand break repair or adaptation in Saccharomyces cerevisiae. Here, we show the conservation of this pathway in mammalian cells. In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop. The oncogenic protein Wip1, a PP2C phosphatase, binds Chk2 and dephosphorylates phospho-Thr68. Consequently, Wip1 opposes Chk2 activation by ATM after ionizing irradiation of cells. In HCT15 colorectal cancer cells corrected for functional Chk2 activity, Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint. These results indicate that Wip1 is one of the phosphatases regulating the activity of Chk2 in response to DNA damage.
我们先前证明，在酿酒酵母中，DNA双链断裂修复或适应后，2C型蛋白磷酸酶（PP2C）Ptc2和Ptc3是DNA检查点失活所必需的。在此，我们展示了该途径在哺乳动物细胞中的保守性。响应DNA损伤时，共济失调毛细血管扩张症突变蛋白（ATM）在苏氨酸68（Thr68）位点磷酸化Chk2肿瘤抑制激酶，使Chk2激酶二聚化并通过T环中的自磷酸化激活。致癌蛋白Wip1是一种PP2C磷酸酶，它结合Chk2并使磷酸化的Thr68去磷酸化。因此，在细胞受到电离辐射后，Wip1会对抗ATM对Chk2的激活作用。在功能Chk2活性得到校正的HCT15结肠癌细胞中，Wip1的过表达抑制了Chk2对G2/M期DNA损伤检查点的作用。这些结果表明，Wip1是响应DNA损伤调节Chk2活性的磷酸酶之一。
