IKKα保护14-3-3σ（一种G2/M细胞周期检查点基因）不发生高甲基化，从而防止其沉默。
IKKalpha shields 14-3-3sigma, a G(2)/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing.
作者信息
Zhu Feng, Xia Xiaojun, Liu Bigang, Shen Jianjun, Hu Yuhui, Person Maria, Hu Yinling
机构信息
Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
出版信息
Mol Cell. 2007 Jul 20;27(2):214-227. doi: 10.1016/j.molcel.2007.05.042.
We recently reported that a large proportion of aggressive squamous cell carcinomas of humans and mice express markedly reduced IKKalpha. However, the role of IKKalpha in maintaining genomic stability is unknown. Here we reported that IKKalpha-deficient keratinocytes had a defect in the G(2)/M cell-cycle arrest in response to DNA damage due to downregulated 14-3-3sigma, a cell cycle checkpoint protein. Trimethylated histone H3 lysine 9 (H3-K9) was found to associate with the histone trimethyltransferase Suv39h1 and DNA methyltransferase Dnmt3a in the methylated 14-3-3sigma locus. Reintroduction of IKKalpha restored the expression of 14-3-3sigma. IKKalpha was found to associate with H3 in 14-3-3sigma, which prevented access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3sigma. IKKalpha mutants that failed to bind to H3 did not restore the expression of 14-3-3sigma. Thus, IKKalpha protects the 14-3-3sigma locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.
我们最近报道，人类和小鼠的大部分侵袭性鳞状细胞癌中IKKα表达显著降低。然而，IKKα在维持基因组稳定性中的作用尚不清楚。在此我们报道，由于细胞周期检查点蛋白14-3-3σ下调，IKKα缺陷的角质形成细胞在对DNA损伤的G(2)/M细胞周期阻滞方面存在缺陷。发现三甲基化组蛋白H3赖氨酸9（H3-K9）与甲基化的14-3-3σ基因座中的组蛋白三甲基转移酶Suv39h1和DNA甲基转移酶Dnmt3a相关联。重新引入IKKα可恢复14-3-3σ的表达。发现IKKα与14-3-3σ中的H3相关联，这阻止了Suv39h1与H3的结合，从而防止了14-3-3σ的高甲基化。无法与H3结合的IKKα突变体不能恢复14-3-3σ的表达。因此，IKKα保护14-3-3σ基因座免于高甲基化，这是角质形成细胞中维持基因组稳定性的一种机制。
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