pRB family proteins are required for H3K27 trimethylation and polycomb repression complexes binding to and silencing p16INK4a tumor suppressor gene
pRB family proteins are required for H3K27 trimethylation and polycomb repression complexes binding to and silencing p16INK4a tumor suppressor gene
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DOI：
10.1101/gad.1499407
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发表时间：
2007-01-01
影响因子：
10.5
通讯作者：
Xiong, Yue
中科院分区：
文献类型：
--
作者：
Kotake, Yojiro;Cao, Ru;Xiong, Yue
遗传学研究表明，Bmi1促进细胞增殖和干细胞自我更新，同时p16(INK4a)表达降低。在这里，我们证明了Polycomb基因EZH2和BMI1抑制了人和小鼠原代细胞中p16的表达，但在缺乏pRb蛋白功能的细胞中没有。P16基因由H3K27甲基化，并与BMI1、RING2和SUZ12结合。PRB家族蛋白的失活取消了H3K27的甲基化，并破坏了BMI1、RING2和SUZ12与p16基因的结合。这些结果提示了一种模型，在该模型中，PRB蛋白招募PRC2来三甲基化p16，启动含有BMI1的PRC1L泛素连接酶复合体来沉默p16。
Genetic studies have demonstrated that Bmi1 promotes cell proliferation and stem cell self-renewal with a correlative decrease of p16(INK4a) expression. Here, we demonstrate that Polycomb genes EZH2 and BMI1 repress p16 expression in human and mouse primary cells, but not in cells deficient for pRB protein function. The p16 locus is H3K27-methylated and bound by BMI1, RING2, and SUZ12. Inactivation of pRB family proteins abolishes H3K27 methylation and disrupts BMI1, RING2, and SUZ12 binding to the p16 locus. These results suggest a model in which pRB proteins recruit PRC2 to trimethylate p16, priming the BMI1-containing PRC1L ubiquitin ligase complex to silence p16.