N⁶-methyladenosine (m⁶A) is the most prevalent modified nucleotide in mRNA, and it has important functions in mRNA regulation. However, our understanding of the specific functions of m⁶A along with its cytosolic readers, the YTHDF proteins, has changed substantially in recent years. The original view was that different m⁶A sites within an mRNA could have different functions depending on which YTHDF paralog was bound to it, with bound YTHDF1 inducing translation, while bound YTHDF2 induced mRNA degradation. As a result, each YTHDF was proposed to have unique physiologic roles that arise from their unique binding properties and regulatory effects on mRNA. More recent data have called much of this into question, showing that all m⁶A sites bind all YTHDF proteins with equal ability, with a single primary function of all three YTHDF proteins to mediate mRNA degradation. Here, we describe the diverse technical concerns that led to the original model being questioned and the newer data that overturned this model and led to the new understanding of m⁶A and YTHDF function. We also discuss how any remaining questions about the functions of the YTHDF proteins can be readily resolved.

中文翻译：

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了解 m6A 结合 YTHDF 蛋白的冗余功能

N ⁶ -甲基腺苷(m ⁶ A)是mRNA中最常见的修饰核苷酸，在mRNA调节中具有重要功能。然而，近年来，我们对 m ⁶ A 及其胞质阅读器 YTHDF 蛋白的特定功能的理解发生了很大变化。最初的观点是，mRNA 内的不同 m ⁶ A 位点可能具有不同的功能，具体取决于与其结合的 YTHDF 旁系同源物，结合的 YTHDF1 诱导翻译，而结合的 YTHDF2 诱导 mRNA 降解。因此，每种 YTHDF 都被认为具有独特的生理作用，这些作用源于其独特的结合特性和对 mRNA 的调节作用。最近的数据对这一点提出了质疑，表明所有 m ⁶ A 位点以相同的能力结合所有 YTHDF 蛋白，所有三种 YTHDF 蛋白都有一个主要功能介导 mRNA 降解。在这里，我们描述了导致原始模型受到质疑的各种技术问题以及推翻该模型并导致对 m ⁶ A 和 YTHDF 函数的新理解的新数据。我们还讨论了如何轻松解决有关 YTHDF 蛋白功能的任何剩余问题。