Dynamic phosphorylation of HP1α regulates mitotic progression in human cells.
Dynamic phosphorylation of HP1α regulates mitotic progression in human cells.
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DOI：
10.1038/ncomms4445
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发表时间：
2014-03-12
影响因子：
16.6
通讯作者：
Prasanth SG
中科院分区：
文献类型：
--
作者：
Chakraborty A;Prasanth KV;Prasanth SG
异染色质蛋白1α (Heterochromatin protein 1α, HP1α)在高阶染色质的建立和维持中起着关键作用，调控着细胞的关键过程，包括中期染色单体内聚和着丝粒组织。然而，HP1α如何控制这些过程尚不清楚。在这里，我们证明了HP1α的翻译后修饰决定了它的有丝分裂功能。HP1α在其n端内被组成性磷酸化，而在铰链域内的磷酸化优先发生在细胞周期的G2/M期。HP1α的铰链磷酸化形式在有丝分裂早期特异性定位于着丝点，这种由NDR1激酶介导的磷酸化是有丝分裂进程和Sgo1与有丝分裂着丝粒结合所必需的。缺乏NDR激酶的细胞显示有丝分裂特异性的HP1α磷酸化缺失，导致前期中期停滞。我们的研究结果表明，NDR激酶在体内G2/M期间催化人类HP1α的铰链特异性磷酸化，并协调准确的染色体排列和有丝分裂进程。
Heterochromatin protein 1α (HP1α), a key player in the establishment and maintenance of higher-order chromatin regulates key cellular processes, including metaphase chromatid cohesion and centromere organization. However, how HP1α controls these processes is not well understood. Here we demonstrate that post-translational modifications of HP1α dictate its mitotic functions. HP1α is constitutively phosphorylated within its N-terminus whereas phosphorylation within the hinge domain occurs preferentially at G2/M phase of the cell cycle. The hinge-phosphorylated form of HP1α specifically localizes to kinetochores during early mitosis and this phosphorylation mediated by NDR1 kinase is required for mitotic progression and for Sgo1 binding to mitotic centromeres. Cells lacking NDR kinase show loss of mitosis-specific phosphorylation of HP1α leading to prometaphase arrest. Our results reveal that NDR kinase catalyzes the hinge-specific phosphorylation of human HP1α during G2/M in vivo and this orchestrates accurate chromosome alignment and mitotic progression.
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