N6-methyladenosine (m6A), the most abundant internal modification on eukaryotic mRNA, and N6, 2′-O-dimethyladenosine (m6Am), are epitranscriptomic marks that function in multiple aspects of posttranscriptional regulation. Fat mass and obesity-associated protein (FTO) can remove both m6A and m6Am; however, little is known about how FTO achieves its substrate selectivity. Here, we demonstrate that ZBTB48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of ZBTB48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. ZBTB48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which ZBTB48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.

中文翻译：

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端粒锌指蛋白 ZBTB48 招募 m6A/m6Am 去甲基酶 FTO 来靶向 RNA


N6-甲基腺苷 (m6A) 是真核 mRNA 上最丰富的内部修饰，而 N6, 2'-O-二甲基腺苷 (m6Am) 是在转录后调控的多个方面发挥作用的表观转录组标记。脂肪量和肥胖相关蛋白（FTO）可以去除 m6A 和 m6Am；然而，人们对 FTO 如何实现其底物选择性知之甚少。在这里，我们证明了 ZBTB48（一种在端粒维持中发挥作用的 C2H2-锌指蛋白）与 FTO 结合，并结合 mRNA 和端粒相关调节 RNA TERRA，以调节 FTO 与靶转录本的功能相互作用。具体而言，ZBTB48 的耗尽会影响 FTO 靶向 m6A/m6Am 修饰位点，改变细胞 m6A/m6Am 水平，从而改变靶 RNA 的衰减率。 ZBTB48 消融还可加速 HCT-116 结直肠癌细胞的生长，并通过控制与 m6A 读取器 IGF2BP2 的 MTA1 mRNA 的结合来调节转移相关蛋白 1 (MTA1) 转录本的 FTO 依赖性调节。因此，我们的研究结果揭示了一种以前未知的转录后调控机制，其中 ZBTB48 协调 m6A/m6Am 去甲基酶 FTO 的 RNA 结合，以控制其靶 RNA 的表达。