Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129.
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
J Biol Chem. 2011 Sep 2;286(35):30462-30470. doi: 10.1074/jbc.M111.273508. Epub 2011 Jul 8.
Chromatin-modifying enzymes play a fundamental role in regulating chromatin structure so that DNA replication is spatially and temporally coordinated. For example, the lysine demethylase 4A/Jumonji domain-containing 2A (KDM4A/JMJD2A) is tightly regulated during the cell cycle. Overexpression of JMJD2A leads to altered replication timing and faster S phase progression. In this study, we demonstrate that degradation of JMJD2A is regulated by the proteasome. JMJD2A turnover is coordinated through the SKP1-Cul1-F-box ubiquitin ligase complex that contains cullin 1 and the F-box and leucine-rich repeat protein 4 (FbxL4). This complex interacted with JMJD2A. Ubiquitin overexpression restored turnover and blocked the JMJD2A-dependent faster S phase progression in a cullin 1-dependent manner. Furthermore, increased ubiquitin levels decreased JMJD2A occupancy and BrdU incorporation at target sites. This study highlights a finely tuned mechanism for regulating histone demethylase levels and emphasizes the need to tightly regulate chromatin modifiers so that the cell cycle occurs properly.
染色质修饰酶在调节染色质结构方面发挥着基本作用，从而使 DNA 复制在时空上协调一致。例如，赖氨酸去甲基酶 4A/包含 Jumonji 结构域的 2A（KDM4A/JMJD2A）在细胞周期中受到严格调控。JMJD2A 的过表达导致复制时间改变和 S 期进程加快。在这项研究中，我们证明了 JMJD2A 的降解受蛋白酶体调控。JMJD2A 的周转通过包含 Cullin 1 和 F-box 和富含亮氨酸重复蛋白 4（FbxL4）的 SKP1-Cul1-F-box 泛素连接酶复合物协调。该复合物与 JMJD2A 相互作用。泛素过表达以 Cullin 1 依赖性方式恢复了周转率，并阻止了 JMJD2A 依赖性更快的 S 期进程。此外，增加的泛素水平降低了靶位点处的 JMJD2A 占有率和 BrdU 掺入。这项研究强调了一种精细调节组蛋白去甲基酶水平的机制，并强调需要严格调控染色质修饰物，以使细胞周期正常发生。
