Dong Zhiwan, Tomkinson Alan E
Molecular and Cell Biology Graduate Program Baltimore, MD 21201-1509, USA.
Nucleic Acids Res. 2006;34(20):5721-279. doi: 10.1093/nar/gkl705. Epub 2006 Oct 12.
Among the three mammalian genes encoding DNA ligases, only the LIG3 gene does not have a homolog in lower eukaryotes. In somatic mammalian cells, the nuclear form of DNA ligase IIIalpha forms a stable complex with the DNA repair protein XRCC1 that is also found only in higher eukaryotes. Recent studies have shown that XRCC1 participates in S phase-specific DNA repair pathways independently of DNA ligase IIIalpha and is constitutively phosphorylated by casein kinase II. In this study we demonstrate that DNA ligase IIIalpha, unlike XRCC1, is phosphorylated in a cell cycle-dependent manner. Specifically, DNA ligase IIIalpha is phosphorylated on Ser123 by the cell division cycle kinase Cdk2 beginning early in S phase and continuing into M phase. Interestingly, treatment of S phase cells with agents that cause oxygen free radicals induces the dephosphorylation of DNA ligase IIIalpha. This oxidative stress-induced dephosphorylation of DNA ligase IIIalpha is dependent upon the ATM (ataxia-telangiectasia mutated) kinase and appears to involve inhibition of Cdk2 and probably activation of a phosphatase.
在编码DNA连接酶的三个哺乳动物基因中，只有LIG3基因在低等真核生物中没有同源物。在哺乳动物体细胞中，DNA连接酶IIIα的核形式与DNA修复蛋白XRCC1形成稳定复合物，而XRCC1也仅在高等真核生物中发现。最近的研究表明，XRCC1独立于DNA连接酶IIIα参与S期特异性DNA修复途径，并被酪蛋白激酶II组成性磷酸化。在本研究中，我们证明与XRCC1不同，DNA连接酶IIIα以细胞周期依赖性方式被磷酸化。具体而言，DNA连接酶IIIα在S期早期开始并持续到M期，被细胞分裂周期激酶Cdk2在Ser123位点磷酸化。有趣的是，用引起氧自由基的试剂处理S期细胞会诱导DNA连接酶IIIα的去磷酸化。这种氧化应激诱导的DNA连接酶IIIα去磷酸化依赖于ATM（共济失调毛细血管扩张突变）激酶，并且似乎涉及对Cdk2的抑制以及可能的磷酸酶激活。
