Drosophila casein kinase I alpha regulates homolog pairing and genome organization by modulating condensin II subunit Cap-H2 levels.
Drosophila casein kinase I alpha regulates homolog pairing and genome organization by modulating condensin II subunit Cap-H2 levels.
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DOI：
10.1371/journal.pgen.1005014
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发表时间：
2015
期刊：
影响因子：
4.5
通讯作者：
Bosco G
中科院分区：
文献类型：
--
作者：
Nguyen HQ;Nye J;Buster DW;Klebba JE;Rogers GC;Bosco G
间期核内染色体的空间组织对于基因表达和表观遗传是重要的。虽然染色体之间的物理相互作用的程度和它们的压实程度在发育过程中和不同的细胞类型之间变化，但尚不清楚染色体相互作用和压实的调节如何与基因组的空间组织相关。果蝇是研究包括同源配对在内的染色体相互作用的极好模型系统。最近的工作表明，凝聚素II管理间期染色体压实和同源配对和凝聚素II活性是由其调节亚基Cap-H2的营业额控制。具体地，Cap-H2是SCFSlimb E3泛素连接酶的靶标，其下调Cap-H2以维持同源染色体配对、染色体长度和适当的核组织。在这里，我们确定酪蛋白激酶I α（CK 1 α）作为Cap-H2的额外负调节因子。CK 1 α耗竭稳定了Cap-H2蛋白，并导致Cap-H2在染色体上积累。与Slimb突变相似，培养细胞、幼虫唾液腺和滋养细胞中的CK 1 α耗竭导致几种凝聚素II依赖性表型，包括着丝粒分散、间期染色体致密化和染色体不配对。此外，CK 1 α功能丧失突变在体内主要抑制凝聚素II突变表型。因此，CK 1 α促进Cap-H2破坏，并通过减弱染色质定位的Cap-H2蛋白来调节核组织。Cap-H2凝聚素II亚基是相间凝聚素II活性所必需的。先前的工作已经表明，低水平的Cap-H2蛋白质在间期是通过SCFSlimb介导的蛋白质周转来实现的，并限制了染色质结合的蛋白质水平。在这里，我们发现酪蛋白激酶I α（CK 1 α）也是通过促进Cap-H2破坏和限制染色质结合的Cap-H2水平来负调节间期凝聚素II活性的。CK 1 α功能丧失导致染色体结构异常，可通过Cap-H2或其他凝聚素亚基突变或缺失抑制。这些观察结果表明，通常，间期凝聚素II水平必须保持较低，以保持适当的间期染色体组织，这种低活性是通过有针对性地破坏Cap-H2来维持的。
The spatial organization of chromosomes within interphase nuclei is important for gene expression and epigenetic inheritance. Although the extent of physical interaction between chromosomes and their degree of compaction varies during development and between different cell-types, it is unclear how regulation of chromosome interactions and compaction relate to spatial organization of genomes. Drosophila is an excellent model system for studying chromosomal interactions including homolog pairing. Recent work has shown that condensin II governs both interphase chromosome compaction and homolog pairing and condensin II activity is controlled by the turnover of its regulatory subunit Cap-H2. Specifically, Cap-H2 is a target of the SCFSlimb E3 ubiquitin-ligase which down-regulates Cap-H2 in order to maintain homologous chromosome pairing, chromosome length and proper nuclear organization. Here, we identify Casein Kinase I alpha (CK1α) as an additional negative-regulator of Cap-H2. CK1α-depletion stabilizes Cap-H2 protein and results in an accumulation of Cap-H2 on chromosomes. Similar to Slimb mutation, CK1α depletion in cultured cells, larval salivary gland, and nurse cells results in several condensin II-dependent phenotypes including dispersal of centromeres, interphase chromosome compaction, and chromosome unpairing. Moreover, CK1α loss-of-function mutations dominantly suppress condensin II mutant phenotypes in vivo. Thus, CK1α facilitates Cap-H2 destruction and modulates nuclear organization by attenuating chromatin localized Cap-H2 protein. The Cap-H2 condensin II subunit is required for interphase condensin II activity. Previous work has shown that low levels of Cap-H2 protein in interphase is achieved by SCFSlimb mediated protein turnover and limits chromatin-bound protein levels. Here we show that Casein Kinase I alpha (CK1α) is also a negative regulator of interphase condensin II activity by promoting Cap-H2 destruction and limiting chromatin-bound Cap-H2 levels. Loss of CK1α function leads to aberrant chromosome structures that are suppressed by mutation or depletion of Cap-H2 or other condensin subunits. These observations suggest that normally, interphase condensin II levels must be kept low in order to maintain proper interphase chromosome organization, and this low activity is maintained by targeted destruction of Cap-H2.