E3 连接酶 CUL3/RDX 通过依赖于 CAL1 的方式泛素化和稳定 CENP-A 来控制着着丝粒的维持。

The E3 ligase CUL3/RDX controls centromere maintenance by ubiquitylating and stabilizing CENP-A in a CAL1-dependent manner.

机构信息

Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH-Alliance, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.

出版信息

Dev Cell. 2014 Mar 10;28(5):508-19. doi: 10.1016/j.devcel.2014.01.031.

DOI:10.1016/j.devcel.2014.01.031

PMID:24636256

Abstract

Centromeres are defined by the presence of the histone H3 variant CENP-A in a subset of centromeric nucleosomes. CENP-A deposition to centromeres depends on a specialized loading factor from yeast to humans that is called CAL1 in Drosophila. Here, we show that CAL1 directly interacts with RDX, an adaptor for CUL3-mediated ubiquitylation. However, CAL1 is not a substrate of the CUL3/RDX ligase but functions as an additional substrate-specifying factor for the CUL3/RDX-mediated ubiquitylation of CENP-A. Remarkably, ubiquitylation of CENP-A by CUL3/RDX does not trigger its degradation but stabilizes CENP-A and CAL1. Loss of RDX leads to a rapid degradation of CAL1 and CENP-A and to massive chromosome segregation defects during development. Essentially, we identified a proteolysis-independent role of ubiquitin conjugation in centromere regulation that is essential for the maintenance of the centromere-defining protein CENP-A and its loading factor CAL1.

摘要

着丝粒是由组蛋白 H3 变体 CENP-A 在一部分着丝粒核小体中存在而定义的。CENP-A 向着丝粒的沉积依赖于从酵母到人中一种特殊的加载因子，在果蝇中称为 CAL1。在这里，我们表明 CAL1 直接与 RDX 相互作用，RDX 是 CUL3 介导的泛素化的衔接子。然而，CAL1 不是 CUL3/RDX 连接酶的底物，而是作为 CUL3/RDX 介导的 CENP-A 泛素化的额外底物特异性因子发挥作用。值得注意的是，CUL3/RDX 对 CENP-A 的泛素化不会触发其降解，而是稳定 CENP-A 和 CAL1。RDX 的缺失导致 CAL1 和 CENP-A 的快速降解，并在发育过程中导致大量染色体分离缺陷。本质上，我们确定了泛素缀合在着丝粒调节中的一种非蛋白水解作用，对于维持着丝粒定义蛋白 CENP-A 和其加载因子 CAL1 是必不可少的。