Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Peking-Tsinghua Center for Life Sciences, Beijing 100871, China.
Cell Chem Biol. 2020 Mar 19;27(3):283-291.e6. doi: 10.1016/j.chembiol.2020.01.002. Epub 2020 Jan 24.
The fat mass and obesity-associated protein (FTO) is the first identified demethylase of the internal RNA modification N-methyladenosine (mA), which also exhibits demethylation activity toward N,2'-O-dimethyladenosine (mA) and N-methyladenosine (mA). Demethylation of mA at specific sites on target transcripts is a key enzymatic function of FTO that modulates diverse physiological and/or pathological processes. However, how FTO selects target RNA and whether additional interaction proteins facilitate this process remain elusive. Herein, via the genetically encoded and site-specific photocrosslinking strategy, we identified the major RNA-binding protein SFPQ as a direct interaction partner of FTO. Our study showed that FTO and SFPQ were located in close proximity throughout the transcriptome and that overexpression of SFPQ led to the demethylation of adjacent mAs, likely through recruiting FTO to these specific RNA sites. These results uncovered a new layer of regulation mechanism that may assist FTO to gain substrate specificity.
肥胖相关基因（FTO）是第一个被鉴定出的内部 RNA 修饰 N6-甲基腺苷（m6A）去甲基酶，它也表现出对 N,2'-O-二甲基腺苷（m6Am）和 N6-甲基腺苷（m6A）的去甲基化活性。在靶转录本的特定位点对 mA 进行去甲基化是 FTO 的一个关键酶促功能，它调节多种生理和/或病理过程。然而，FTO 如何选择靶 RNA，以及是否有其他相互作用蛋白促进这一过程，仍然难以捉摸。在此，我们通过遗传编码和位点特异性光交联策略，鉴定了主要的 RNA 结合蛋白 SFPQ 是 FTO 的一个直接相互作用伙伴。我们的研究表明，FTO 和 SFPQ 在整个转录组中紧密相邻，SFPQ 的过表达导致相邻 mA 的去甲基化，可能是通过将 FTO 招募到这些特定的 RNA 位点。这些结果揭示了一种新的调控机制，可能有助于 FTO 获得底物特异性。
