Department of Biochemistry, Duke University School of Medicine, Durham NC 27710, USA.
Trinity College of Arts and Sciences, Duke University, Durham, NC 27710, USA.
Cell Rep. 2022 Aug 30;40(9):111293. doi: 10.1016/j.celrep.2022.111293.
N-methyladenosine (mA) is deposited co-transcriptionally on thousands of cellular mRNAs and plays important roles in mRNA processing and cellular function. mA is particularly abundant within the brain and is critical for neurodevelopment. However, the mechanisms through which mA contributes to brain development are incompletely understood. RBM45 acts as an mA-binding protein that is highly expressed during neurodevelopment. We find that RBM45 binds to thousands of cellular RNAs, predominantly within intronic regions. Rbm45 depletion disrupts the constitutive splicing of a subset of target pre-mRNAs, leading to altered mRNA and protein levels through both mA-dependent and mA-independent mechanisms. Finally, we find that RBM45 is necessary for neuroblastoma cell differentiation and that its depletion impacts the expression of genes involved in several neurodevelopmental signaling pathways. Altogether, our findings show a role for RBM45 in controlling mRNA processing and neuronal differentiation, mediated in part by the recognition of methylated RNA.
N6-甲基腺苷（m6A）在数千个细胞 mRNA 上共转录沉积，并在 mRNA 加工和细胞功能中发挥重要作用。m6A 在大脑中特别丰富，对神经发育至关重要。然而，m6A 促进大脑发育的机制尚不完全清楚。RBM45 作为一种 m6A 结合蛋白，在神经发育过程中高度表达。我们发现 RBM45 结合到数千个细胞 RNA 上，主要位于内含子区域。Rbm45 耗竭会破坏一组靶前体 mRNA 的组成性剪接，导致通过 m6A 依赖和非依赖机制改变 mRNA 和蛋白质水平。最后，我们发现 RBM45 对于神经母细胞瘤细胞分化是必需的，其耗竭会影响参与几个神经发育信号通路的基因的表达。总之，我们的研究结果表明 RBM45 在控制 mRNA 处理和神经元分化中发挥作用，部分是通过识别甲基化 RNA 来介导的。
