Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
J Biol Chem. 2020 Dec 11;295(50):17060-17070. doi: 10.1074/jbc.RA120.014704. Epub 2020 Oct 2.
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 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 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.
CARM1 是一种蛋白精氨酸甲基转移酶（PRMT），作为许多转录程序的共激活因子发挥作用。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 小鼠中的 H3R17me2a 总水平并没有显著降低，表明其他 PRMT（s）可能弥补了这种损失。因此，我们进行了 I 型 PRMT 的筛选，结果表明 PRMT6 也可以沉积 H3R17me2a 标记。CARM1 敲除小鼠在围产期致死，并表现出胎儿大小减小，而 PRMT6 敲除小鼠是存活的，这允许生成双重敲除。CARM1 和 PRMT6 均缺失的胚胎明显小于 CARM1 缺失的胚胎，这提供了冗余的证据。来自双重敲除胚胎的小鼠胚胎成纤维细胞（MEFs）在有丝分裂期间显示缺乏 H3R17me2a 标记，并出现更多的 DNA 损伤迹象。此外，使用 CARM1 和 PRMT6 抑制剂的组合抑制 WT MEFs 的细胞增殖，表明 CARM1 和 PRMT6 抑制之间存在协同作用。这些研究提供了直接证据表明 PRMT6 也沉积 H3R17me2a 标记，并与 CARM1 冗余。
