Medical Faculty, Institute of Biochemistry, Friedrichstrasse 24, Justus-Liebig-University, 35392 Giessen, Germany.
Mol Cell. 2010 Feb 26;37(4):503-15. doi: 10.1016/j.molcel.2010.01.018.
The IKK-related kinase IKKepsilon contributes to the antiviral response and can function as an oncogene that is frequently amplified in breast cancer. Here we report on an additional role of IKKepsilon as a mediator protecting from DNA-damage-induced cell death. Genotoxic stress allows for kinase-dependent entry of IKKepsilon into the nucleus, where IKKepsilon-dependent PML phosphorylation is a prerequisite for retention of this kinase in PML nuclear bodies. Within these subnuclear structures IKKepsilon inducibly colocalizes with TOPORS, which functions as a SUMO E3 ligase mediating SUMOylation of IKKepsilon at lysine 231. SUMO modification of IKKepsilon is required to trigger phosphorylation of nuclear substrates including NF-kappaB p65, thereby contributing to the antiapoptotic function of NF-kappaB in response to DNA damage.
IKK 相关激酶 IKKε有助于抗病毒反应，并且可以作为癌基因发挥作用，其在乳腺癌中经常被扩增。在这里，我们报告了 IKKε 的另一个作用，即作为一种保护细胞免受 DNA 损伤诱导的细胞死亡的介质。遗传毒性应激允许 IKKε 在激酶依赖性的情况下进入细胞核，在细胞核中，IKKε 依赖性的 PML 磷酸化是将这种激酶保留在 PML 核体中的前提。在这些亚核结构中，IKKε 可诱导性地与 TOPORS 共定位，TOPORS 作为 SUMO E3 连接酶，介导 IKKε 在赖氨酸 231 处的 SUMO 化。IKKε 的 SUMO 修饰对于触发包括 NF-κB p65 在内的核底物的磷酸化是必需的，从而有助于 NF-κB 在应对 DNA 损伤时的抗凋亡功能。
