Catalytic function of the PR-Set7 histone H4 lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability
Catalytic function of the PR-Set7 histone H4 lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability
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DOI：
10.1074/jbc.m710579200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Rice, Judd C.
中科院分区：
文献类型：
--
作者：
Houston, Sabrina I.;McManus, Kirk J.;Rice, Judd C.
组蛋白修饰酶在调节染色质动力学中起关键作用。在这份报告中，我们证明了这些酶之一，PR-Set 7，及其相应的组蛋白修饰，组蛋白H4赖氨酸20（H4 K20）的单甲基化，在哺乳动物细胞中显示出不同的细胞周期谱：低G（1），增加在晚期S期和G（2），并从早中期到后期最大。PR-Set 7和单甲基化H4 K20的缺乏导致几种不同哺乳动物细胞类型中的许多异常表型。这些包括细胞无法通过G（2），整体染色体凝聚失败，异常中心体扩增和大量DNA损伤。通过采用催化死显性负PR-Set 7突变体，我们发现，它的单甲基转移酶活性是防止这些表型所必需的。重要的是，我们证明了与PR-Set 7酶功能丧失相关的所有异常表型独立于p53发生。总的来说，我们的研究结果表明，PR-Set 7酶活性对于哺乳动物细胞周期进展和维持基因组稳定性是必不可少的，最有可能是通过单甲基化组蛋白H4 K20。我们的研究结果预测，这一途径的改变可能会导致总染色体畸变和非整倍体。
Histone-modifying enzymes play a critical role in modulating chromatin dynamics. In this report we demonstrate that one of these enzymes, PR-Set7, and its corresponding histone modification, the monomethylation of histone H4 lysine 20 (H4K20), display a distinct cell cycle profile in mammalian cells: low at G(1), increased during late S phase and G(2), and maximal from prometaphase to anaphase. The lack of PR-Set7 and monomethylated H4K20 resulted in a number of aberrant phenotypes in several different mammalian cell types. These include the inability of cells to progress past G(2), global chromosome condensation failure, aberrant centrosome amplification, and substantial DNA damage. By employing a catalytically dead dominant negative PR-Set7 mutant, we discovered that its mono-methyltransferase activity was required to prevent these phenotypes. Importantly, we demonstrate that all of the aberrant phenotypes associated with the loss of PR-Set7 enzymatic function occur independently of p53. Collectively, our findings demonstrate that PR-Set7 enzymatic activity is essential for mammalian cell cycle progression and for the maintenance of genomic stability, most likely by monomethylating histone H4K20. Our results predict that alterations of this pathway could result in gross chromosomal aberrations and aneuploidy.