RNA modifications have recently emerged as an important layer of gene regulation. N6‐methyladenosine (m⁶A) is the most prominent modification on eukaryotic messenger RNA and has also been found on noncoding RNA , including ribosomal and small nuclear RNA . Recently, several m⁶A methyltransferases were identified, uncovering the specificity of m⁶A deposition by structurally distinct enzymes. In order to discover additional m⁶A enzymes, we performed an RNA i screen to deplete annotated orthologs of human methyltransferase‐like proteins (METTL s) in Drosophila cells and identified CG 9666, the ortholog of human METTL 5. We show that CG 9666 is required for specific deposition of m⁶A on 18S ribosomal RNA via direct interaction with the Drosophila ortholog of human TRMT 112, CG 12975. Depletion of CG 9666 yields a subsequent loss of the 18S rRNA m⁶A modification, which lies in the vicinity of the ribosome decoding center; however, this does not compromise rRNA maturation. Instead, a loss of CG 9666‐mediated m⁶A impacts fly behavior, providing an underlying molecular mechanism for the reported human phenotype in intellectual disability. Thus, our work expands the repertoire of m⁶A methyltransferases, demonstrates the specialization of these enzymes, and further addresses the significance of ribosomal RNA modifications in gene expression and animal behavior.

中文翻译：

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18S 核糖体 RNA m6 A 甲基转移酶 Mettl5 是果蝇正常行走行为所必需的。

RNA 修饰最近已成为基因调控的一个重要层面。N6-甲基腺苷 (m ⁶ A) 是真核信使 RNA 上最显着的修饰，也在非编码 RNA 上发现，包括核糖体和小核 RNA。最近，鉴定了几种 m ⁶ A 甲基转移酶，揭示了结构不同的酶对 m ⁶ A 沉积的特异性。为了发现额外的 m ^{6 A 酶，我们进行了 RNA i 筛选，以耗尽}果蝇细胞中人类甲基转移酶样蛋白 (METTL s) 的注释直系同源物，并鉴定了人类 METTL 5 的直系同源物 CG 9666。我们发现 CG 9666需要 m ^{6的特定沉积}18S 核糖体 RNA 上的 A 通过与人 TRMT 112、CG 12975 的果蝇直系同源物直接相互作用。 CG 9666 的消耗导致随后丢失位于核糖体解码中心附近的 18S rRNA m ⁶ A 修饰；然而，这不会影响 rRNA 的成熟。相反，CG 9666 介导的 m ⁶ A 的缺失会影响飞行行为，从而为报告的人类智力障碍表型提供潜在的分子机制。因此，我们的工作扩展了 m ⁶ A 甲基转移酶的库，证明了这些酶的特化，并进一步说明了核糖体 RNA 修饰在基因表达和动物行为中的重要性。