CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere.
CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere.
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DOI：
10.1016/j.devcel.2015.01.024
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发表时间：
2015-03-09
影响因子：
11.8
通讯作者：
Kitagawa K
中科院分区：
文献类型：
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作者：
Niikura Y;Kitagawa R;Ogi H;Abdulle R;Pagala V;Kitagawa K
CENP-A是一种着丝粒特异性组蛋白H3变体，其表观遗传学决定着丝粒身份以确保着丝粒组装和适当的染色体分离，但其在着丝粒异染色质内特异性定位的精确机制仍然不清楚。我们已经发现CUL 4A-RBX 1-COPS 8 E3连接酶活性是CENP-A在赖氨酸124（K124）上的泛素化和CENP-A着丝粒定位所需的。CENP-A的突变K124 R减少了与HJURP（CENP-A特异性组蛋白伴侣）的相互作用，并消除了CENP-A对着丝粒的定位。单泛素的添加足以将CENP-A K124 R恢复到着丝粒并与HJURP相互作用，表明“信号传导”泛素化是CENP-A在着丝粒处加载所需的。CUL 4A-RBX 1复合物是装载新合成的CENP-A并将预组装的CENP-A维持在着丝粒所必需的。因此，由CUL 4A-RBX 1-COPS 8复合物介导的CENP-A K124 R泛素化对于CENP-A在着丝粒处的沉积是必需的。
CENP-A is a centromere-specific histone H3 variant that epigenetically determines centromere identity to ensure kinetochore assembly and proper chromo-some segregation, but the precise mechanism of its specific localization within centromeric heterochromatin remains obscure. We have discovered that CUL4A-RBX1-COPS8 E3 ligase activity is required for CENP-A ubiquitylation on lysine 124 (K124) and CENP-A centromere localization. A mutation of CENP-A, K124R, reduces interaction with HJURP (a CENP-A-specific histone chaperone) and abrogates localization of CENP-A to the centromere. Addition of monoubiquitin is sufficient to restore CENP-A K124R to centromeres and the interaction with HJURP, indicating that “signaling” ubiquitylation is required for CENP-A loading at centromeres. The CUL4A-RBX1 complex is required for loading newly synthesized CENP-A and maintaining preassembled CENP-A at centromeres. Thus, CENP-A K124R ubiquitylation, mediated by the CUL4A-RBX1-COPS8 complex, is essential for CENP-A deposition at the centromere.