Polycomb protein SCML2 regulates the cell cycle by binding and modulating CDK/CYCLIN/p21 complexes.
Polycomb protein SCML2 regulates the cell cycle by binding and modulating CDK/CYCLIN/p21 complexes.
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DOI：
10.1371/journal.pbio.1001737
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发表时间：
2013-12
期刊：
影响因子：
9.8
通讯作者：
Reinberg D
中科院分区：
文献类型：
--
作者：
Lecona E;Rojas LA;Bonasio R;Johnston A;Fernández-Capetillo O;Reinberg D
一个转录非依赖性的作用，确定为人类多梳组蛋白SCML 2B在调节细胞周期。在G1早期，SCML 2B与p21协同抑制CDK 2/CYCE复合物，导致延迟进入S期。Polycomb group（PcG）蛋白是参与发育和分化的基因的转录抑制因子，并且还维持参与细胞周期的关键基因的抑制，从而间接调节细胞增殖。人SCML 2基因是果蝇PcG蛋白SCM的哺乳动物同源物，编码两种蛋白质亚型：与染色质结合的SCML 2A和主要为核质的SCML 2B。在这里，我们纯化了SCML 2B，发现它与CDK/CYCLIN/p21和p27形成稳定的复合物，增强了p21/p27的抑制作用。SCML 2B通过稳定p21并促进其与CDK 2/CYCE的相互作用参与G1/S检查点，导致激酶活性降低并抑制G1期进展。反过来，CDK/细胞周期蛋白复合物磷酸化SCML 2，SCML 2B与CDK 2的相互作用通过细胞周期调节。这些发现突出了哺乳动物细胞记忆的Polycomb系统和细胞周期机制之间的直接串扰。发育和分化的过程需要基因表达程序与细胞增殖的精密协调。Polycomb蛋白质组是重要的发育调节剂，迄今为止，大多数研究都集中在它们参与维持发育过程中基因的表观遗传沉默以及干细胞的自我更新和分化。到目前为止，我们已经看到Polycomb蛋白通过染色质修饰影响细胞周期调节因子的转录状态。在这里，我们描述了一个人Polycomb组蛋白在调节细胞周期的转录独立的功能。我们发现，Polycomb组蛋白SCML 2直接调节细胞从G1期进入S期的进展，通过与p21合作，抑制CDK 2/CYCE复合物在G1早期的激活。该功能由不与Polycomb复合物PRC 1相互作用的SCML 2的“B”同种型执行。此外，SCML 2B磷酸化通过细胞周期调节，并且部分依赖于CDK 1和CDK 2。这些发现突出了哺乳动物细胞记忆和细胞周期机制的Polycomb系统之间的直接串扰，提供了深入了解哺乳动物Polycomb系统的新功能。
A transcription-independent role is identified for the human Polycomb group protein SCML2B in regulating the cell cycle. SCML2B cooperates with p21 to inhibit CDK2/CYCE complexes during early G1, resulting in delayed entry into S phase. Polycomb group (PcG) proteins are transcriptional repressors of genes involved in development and differentiation, and also maintain repression of key genes involved in the cell cycle, indirectly regulating cell proliferation. The human SCML2 gene, a mammalian homologue of the Drosophila PcG protein SCM, encodes two protein isoforms: SCML2A that is bound to chromatin and SCML2B that is predominantly nucleoplasmic. Here, we purified SCML2B and found that it forms a stable complex with CDK/CYCLIN/p21 and p27, enhancing the inhibitory effect of p21/p27. SCML2B participates in the G1/S checkpoint by stabilizing p21 and favoring its interaction with CDK2/CYCE, resulting in decreased kinase activity and inhibited progression through G1. In turn, CDK/CYCLIN complexes phosphorylate SCML2, and the interaction of SCML2B with CDK2 is regulated through the cell cycle. These findings highlight a direct crosstalk between the Polycomb system of cellular memory and the cell-cycle machinery in mammals. The processes of development and differentiation require an exquisite coordination of the gene expression program with the proliferation of the cells. The Polycomb group of proteins are important development regulators and most research to date has focused on their involvement in maintaining epigenetic silencing of genes during development and the self-renewal and differentiation of stem cells. Up to now, we've seen that Polycomb proteins influence the transcriptional status of cell-cycle regulators via chromatin modifications. Here we describe a transcription-independent function for a human Polycomb group protein in regulating the cell cycle. We show that the Polycomb group protein SCML2 directly regulates the progression of cells from G1 into S phase by cooperating with p21 to restrain the activation of CDK2/CYCE complexes in early G1. This function is carried out by the “B” isoform of SCML2 that does not interact with the Polycomb complex PRC1. Further, SCML2B phosphorylation is regulated through the cell cycle and is partly dependent on CDK1 and CDK2. These findings highlight a direct crosstalk between the Polycomb system of cellular memory and cell-cycle machinery in mammals, providing insight into novel functions of the mammalian Polycomb system.
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影响因子：
5.3
作者：
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Mueller, Christoph W.
影响因子：
37.3
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