The mechanism of YTHDF2 accelerating polyadenylation and degradation of RNA

YTHDF2 binds to m6A modification on RNA and recruit CCR4-NOT adenylate cyclase complex through direct interaction with CNOT1 to accelerate polyadenylation and degradation of RNA, according research using recombinant mouse proteins.

On August 25th, the international academic journal Nature Communications online published the latest study collaborate by Wu Ligang study group from the Shanghai Life Science Institute of Biochemistry and Cell Biology Institute of the National Academy of Sciences Protein Science Center (Shanghai) and Life Sciences and Ma Jinbiao study group from School of life sciences of Fudan University - YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. The study found that YTHDF2 promotes RNA containing m6A to degrade by directly recruiting CCR4-NOT complex adenylate cyclase complex.

Methylation located at the site of adenylate N6 (m6A) is the most common type of modification inside of eukaryotic mRNA and the long non-coding RNA. Recent studies show that m6A is a dynamically-reversible RNA modification which plays an important role in many biological processes, including stem cell self-renewal and differentiation, reproductive mice, yeast meiosis and the like. m6A can be identified by a variety of intracellular proteins and can binds to them, thereby regulating the processing, translation and stability of RNA. Wherein m6A binding to protein YTHDF family can contribute to the degradation of RNA, but the RNA degradation pathway and molecular mechanism mediated by it are still unknown. The research made use of momentary inducible expression system to monitor the degradation process of RNA, and it was found that m6A modification or YTHDF2 binding all can promote the RNA deadenylation (i.e., the removal of RNA 3 'end poly (A) tail).

Researchers conducted interaction detection and functional screening on a variety of adenylate cyclase in cells of mammalian and ultimately determined the CCR4-NOT adenylate cyclase complex is the effector which mediates the process. CCR4-NOT is a nine-subunit complex comprising adenylate cyclase CAF1 and CCR4 which have catalytic activity and scaffold protein CNOT1. Further studies have shown YTHDF2 directly interacts with SH domain of CNOT1 through its N-terminal region to recruit CCR4-NOT complex. As the main adenylate cyclase, CAF1 and CCR4 promote the polyadenylation and degradation of m6A RNA.

Interestingly, not only m6A modification located in mRNA 3' non-translated region can lead to degradation of mRNA, m6A modification located at protein reading frame (ORF) of mRNA, and m6A modification in long non-coding RNA in are also leads to its RNA degradation by the same mechanism. The study reveals the molecular mechanism of m6A modification- mediated degradation of mRNA and lncRNA, doing more help for clarifying the phenomenon of RNA modification regulating gene expression. Flarebio provides good-quality recombinant proteins like recombinant Cdh9 at competitive prices.