Genetic evidence for partial redundancy between the arginine methyltransferases CARM1 and PRMT6
Genetic evidence for partial redundancy between the arginine methyltransferases CARM1 and PRMT6
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DOI：
10.1074/jbc.ra120.014704
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发表时间：
2020-12-11
影响因子：
4.8
通讯作者：
Bedford, Mark T.
中科院分区：
文献类型：
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作者：
Cheng, Donghang;Gao, Guozhen;Bedford, Mark T.
CARM1是一种蛋白质精氨酸甲基转移酶（PRMT），在许多转录程序中充当共激活因子。CARM1通过在其调节的基因启动子附近沉积H3R17me2a组蛋白标记来协调这种共激活因子活性。然而，CARM1 KO小鼠中H3R17me2a的总水平没有显著降低，表明其他PRMT可能补偿这种损失。因此，我们进行了I型PRMT的筛选，其显示PRMT 6也可以在体外存款H3R17 me2a标记。CARM1敲除小鼠是围产期致死的，并显示胎儿尺寸减小，而PRMT6缺失小鼠是存活的，这允许产生双敲除。对于CARM1和PRMT6都无效的胚胎明显小于CARM1无效胚胎，提供了冗余的体内证据。来自双敲除胚胎的小鼠胚胎成纤维细胞（MEF）在有丝分裂期间显示出H3R17me2a标记的缺失和DNA损伤的增加的迹象。此外，使用CARM1和PRMT6抑制剂的组合抑制WT MEF的细胞增殖，表明CARM1和PRMT6抑制之间的协同效应。这些研究提供了PRMT6也沉积H3R17me2a标记并与CARM1冗余作用的直接证据。
CARM1 is a protein arginine methyltransferase (PRMT) that acts as a coactivator in a number of transcriptional programs. CARM1 orchestrates this coactivator activity in part by depositing the H3R17me2a histone mark in the vicinity of gene promoters that it regulates. However, the gross levels of H3R17me2a in CARM1 KO mice did not significantly decrease, indicating that other PRMT(s) may compensate for this loss. We thus performed a screen of type I PRMTs, which revealed that PRMT6 can also deposit the H3R17me2a mark in vitro. CARM1 knockout mice are perinatally lethal and display a reduced fetal size, whereas PRMT6 null mice are viable, which permits the generation of double knockouts. Embryos that are null for both CARM1 and PRMT6 are noticeably smaller than CARM1 null embryos, providing in vivo evidence of redundancy. Mouse embryonic fibroblasts (MEFs) from the double knockout embryos display an absence of the H3R17me2a mark during mitosis and increased signs of DNA damage. Moreover, using the combination of CARM1 and PRMT6 inhibitors suppresses the cell proliferation of WT MEFs, suggesting a synergistic effect between CARM1 and PRMT6 inhibitions. These studies provide direct evidence that PRMT6 also deposits the H3R17me2a mark and acts redundantly with CARM1.