The role of PR-Set7 in replication licensing depends on Suv4-20h
The role of PR-Set7 in replication licensing depends on Suv4-20h
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DOI：
10.1101/gad.195636.112
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发表时间：
2012-12-01
影响因子：
10.5
通讯作者：
Reinberg, Danny
中科院分区：
文献类型：
--
作者：
Beck, David B.;Burton, Adam;Reinberg, Danny
PR-Set 7是负责H4 K20单甲基化（H4 K20 me 1）的唯一单甲基转移酶，H4 K20单甲基化是Suv 4 - 20 h1/h2进一步甲基化的底物。PR-Set 7是正常细胞周期进程所必需的，并且作为细胞周期和DNA损伤的函数受到CRL 4（Cdt 2）泛素连接酶复合物的降解。本报告表明，PR-Set 7是一个重要的下游效应的CRL 4（Cdt 2）功能的DNA复制许可的起点，依赖于Suv 4 - 20 h1/2活性。异常再复制与H4 K20 me 1水平降低和H4 K20三甲基化（H4 K20 me 3）水平升高相关。在通常缺乏Suv 4 -20的小鼠胚胎中表达抗降解PR-Set 7突变体不会损害发育或细胞周期进程，除非Suv 4 - 20 h共表达。PR-Set 7靶向人工基因座导致以依赖于Suv 4 - 20 h和H4 K20 me 3的方式募集起源识别复合物（ORC）。与此一致，H4 K20甲基化状态通过ORC 1和ORCA/LRWD 1的结合特性在招募ORC中起直接作用。因此，协调H4 K20甲基化的状态对于在高等真核生物中正确选择DNA复制起点至关重要。
PR-Set7 is the sole monomethyltransferase responsible for H4K20 monomethylation (H4K20me1) that is the substrate for further methylation by Suv4-20h1/h2. PR-Set7 is required for proper cell cycle progression and is subject to degradation by the CRL4(Cdt2) ubiquitin ligase complex as a function of the cell cycle and DNA damage. This report demonstrates that PR-Set7 is an important downstream effector of CRL4(Cdt2) function during origin of DNA replication licensing, dependent on Suv4-20h1/2 activity. Aberrant rereplication correlates with decreased levels of H4K20me1 and increased levels of H4K20 trimethylation (H4K20me3). Expression of a degradation-resistant PR-Set7 mutant in the mouse embryo that is normally devoid of Suv4-20 does not compromise development or cell cycle progression unless Suv4-20h is coexpressed. PR-Set7 targeting to an artificial locus results in recruitment of the origin recognition complex (ORC) in a manner dependent on Suv4-20h and H4K20me3. Consistent with this, H4K20 methylation status plays a direct role in recruiting ORC through the binding properties of ORC1 and ORCA/LRWD1. Thus, coordinating the status of H4K20 methylation is pivotal for the proper selection of DNA replication origins in higher eukaryotes.