HJURP的磷酸化和DNA结合决定了其着丝粒募集以及在CenH3（CENP - A）装载中的功能。
Phosphorylation and DNA binding of HJURP determine its centromeric recruitment and function in CenH3(CENP-A) loading.
作者信息
Müller Sebastian, Montes de Oca Rocio, Lacoste Nicolas, Dingli Florent, Loew Damarys, Almouzni Geneviève
机构信息
Institut Curie, Centre de Recherche, Paris 75248, France; CNRS, UMR3664, Paris 75248, France; Equipe Labellisée Ligue contre le Cancer, UMR3664, Paris 75248, France; UPMC, UMR3664, Paris 75248, France; Sorbonne University, Paris 75005, France.
Institut Curie, Centre de Recherche, Paris 75248, France; Laboratory of Proteomic Mass Spectrometry, 75248 Paris Cedex 05, France.
出版信息
Cell Rep. 2014 Jul 10;8(1):190-203. doi: 10.1016/j.celrep.2014.06.002. Epub 2014 Jul 4.
Centromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals, centromeric CenH3(CENP-A) deposition requires its dedicated chaperone HJURP and occurs during telophase/early G1. We find that the cell-cycle-dependent recruitment of HJURP to centromeres depends on its timely phosphorylation controlled via cyclin-dependent kinases. A nonphosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3(CENP-A) at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3(CENP-A) deposition by a mechanism involving a unique DNA-binding domain. With our findings, we propose a model wherein (1) the phosphorylation state of HJURP controls its centromeric recruitment in a cell-cycle-dependent manner, and (2) HJURP binding to DNA is a mechanistic determinant in CenH3(CENP-A) loading.
着丝粒由组蛋白H3变体CenH3的存在表观遗传定义，对于确保正确的染色体分离至关重要。在哺乳动物中，着丝粒CenH3（CENP-A）的沉积需要其专用伴侣蛋白HJURP，并发生在末期/早期G1期。我们发现，HJURP细胞周期依赖性招募到着丝粒取决于其通过细胞周期蛋白依赖性激酶控制的及时磷酸化。一种不可磷酸化的HJURP突变体在S期和G2期过早定位于着丝粒。这种不受调控的靶向导致CenH3（CENP-A）在着丝粒处过早加载，随后出现细胞周期延迟。一旦被招募到着丝粒，HJURP通过涉及独特DNA结合结构域的机制促进CenH3（CENP-A）的沉积。基于我们的发现，我们提出了一个模型，其中（1）HJURP的磷酸化状态以细胞周期依赖性方式控制其着丝粒招募，并且（2）HJURP与DNA的结合是CenH3（CENP-A）加载的机制决定因素。
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