Scmh1 has E3 ubiquitin ligase activity for Geminin and histone H2A and regulates Geminin stability directly or indirectly via transcription repression of Hoxa9 and Hoxb4
Scmh1 has E3 ubiquitin ligase activity for Geminin and histone H2A and regulates Geminin stability directly or indirectly via transcription repression of Hoxa9 and Hoxb4
复制标题
Scmh1 对 Geminin 和组蛋白 H2A 具有 E3 泛素连接酶活性，并通过 Hoxa9 和 Hoxb4 的转录抑制直接或间接调节 Geminin 稳定性
DOI：
10.1128/mcb.00974-12
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
J. & Takihara Y
中科院分区：
文献类型：
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作者：
Yasunaga;S.;Ohtsubo;M.;Ohno;Y.;Saeki;K.;Kurogi. T.;Tanaka-Okamoto;M.;Ishizaki;H.;Shirai;M.;Mihara;K.;Brock;H. W.;Miyoshi;J. & Takihara Y
Polycomb-group（PcG）complex 1作为E3泛素连接酶，用于组蛋白H2 A沉默转录和双生蛋白调节其稳定性。Scmh 1是PcG复合物1的亚化学计量组分，其为复合物提供了双生蛋白的相互作用结构域。Scmh 1是不稳定的，通过泛素-蛋白酶体系统进行调节，但其分子作用尚不清楚，因此我们产生Scmh 1缺陷小鼠来阐明其功能。Scmh 1的缺失导致Hoxb 4和Hoxa 9的去抑制，Hoxb 4和Hoxa 9是造血细胞中PcG复合物1介导的转录沉默的直接靶点。双敲低Hoxb 4和Hoxa 9或转导显性失活的Hoxb 4 N →A突变体引起双生蛋白积累。去阻遏的Hoxa 9的转录下调也导致双生蛋白积累。缺乏双生蛋白结合域的Scmh 1的转导恢复了Hoxb 4和Hoxa 9的去抑制表达，但没有下调双生蛋白样全长Scmh 1。Hoxb 4和Hoxa 9中的每一个都可以与Roc 1-Ddb 1-Cul 4a形成复合物以充当双生蛋白的E3泛素连接酶。我们认为，双生蛋白失调可能会恢复去抑制Hoxb 4和Hoxa 9在Scmh 1缺陷小鼠。这些发现表明，PcG和Hox基因的一个子集组成了一个自我平衡的调节系统，决定geminin的表达水平。
Polycomb-group (PcG) complex 1 acts as an E3 ubiquitin ligase both for histone H2A to silence transcription and for geminin to regulate its stability. Scmh1 is a substoichiometric component of PcG complex 1 that provides the complex with an interaction domain for geminin. Scmh1 is unstable and regulated through the ubiquitin-proteasome system, but its molecular roles are unknown, so we generated Scmh1-deficient mice to elucidate its function. Loss of Scmh1 caused derepression of Hoxb4 and Hoxa9, direct targets of PcG complex 1-mediated transcriptional silencing in hematopoietic cells. Double knockdown of Hoxb4 and Hoxa9 or transduction of a dominant-negative Hoxb4N→A mutant caused geminin accumulation. Age-related transcriptional downregulation of derepressed Hoxa9 also leads to geminin accumulation. Transduction of Scmh1 lacking a geminin-binding domain restored derepressed expression of Hoxb4 and Hoxa9 but did not downregulate geminin like full-length Scmh1. Each of Hoxb4 and Hoxa9 can form a complex with Roc1-Ddb1-Cul4a to act as an E3 ubiquitin ligase for geminin. We suggest that geminin dysregulation may be restored by derepressed Hoxb4 and Hoxa9 in Scmh1-deficient mice. These findings suggest that PcG and a subset of Hox genes compose a homeostatic regulatory system for determining expression level of geminin.