小柯机器人

瑞士日内瓦大学Ramesh S. Pillai、David Homolka研究组合作取得一项新成果。经过不懈努力，他们发现剪接位点m6A甲基化通过阻止U2AF35结合从而抑制RNA剪接。2021年4月29日出版的《细胞》在线发表了这项成果。

研究人员发现秀丽隐杆线虫RNA N⁶-甲基腺苷（m⁶A）修饰酶METT-10（小鼠METTL16的直系同源物） 通过对S-腺苷甲硫氨酸（SAM）合成酶pre-mRNA 3'剪接位点（AG）进行了m⁶A修饰，从而抑制了其正确剪接和蛋白质产生。

该机制由丰富饮食触发，并充当m⁶A的介导开关，以停止SAM的产生并调节其体内平衡。尽管哺乳动物SAM合成酶pre-mRNA不受此机制调控，但研究显示3'剪接位点m6A的剪接抑制在哺乳动物中也是保守的。该修饰通过阻止必需剪接因子U2AF35识别3'剪接位点而起作用。研究人员揭示了利用剪接位点m6A进行剪接调控的古老机制。

据介绍，RNA m6A修饰可用于改变mRNA的命运。

附：英文原文

Title: Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing

Author: Mateusz Mendel, Kamila Delaney, Radha Raman Pandey, Kuan-Ming Chen, Joanna M. Wenda, Cathrine Broberg Vgb, Florian A. Steiner, David Homolka, Ramesh S. Pillai

Issue&Volume: 2021-04-29

Abstract: The N6-methyladenosine (m6A) RNA modification is used widely to alter the fate of mRNAs. Here we demonstrate that the C. elegans writer METT-10 (the ortholog of mouse METTL16) deposits an m6A mark on the 3′ splice site (AG) of the S-adenosylmethionine (SAM) synthetase pre-mRNA, which inhibits its proper splicing and protein production. The mechanism is triggered by a rich diet and acts as an m6A-mediated switch to stop SAM production and regulate its homeostasis. Although the mammalian SAM synthetase pre-mRNA is not regulated via this mechanism, we show that splicing inhibition by 3′ splice site m6A is conserved in mammals. The modification functions by physically preventing the essential splicing factor U2AF35 from recognizing the 3′ splice site. We propose that use of splice-site m6A is an ancient mechanism for splicing regulation.

DOI: 10.1016/j.cell.2021.03.062

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00435-9