Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, 00185, Italy.
Center for Life Nano- & Neuro-Science@Sapienza, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, 00161, Italy.
Nat Commun. 2023 Apr 5;14(1):1898. doi: 10.1038/s41467-023-37578-7.
N6-Methyladenosine (mA) is well-known for controlling different processes of linear RNA metabolism. Conversely, its role in the biogenesis and function of circular RNAs (circRNAs) is still poorly understood. Here, we characterize circRNA expression in the pathological context of rhabdomyosarcoma (RMS), observing a global increase when compared to wild-type myoblasts. For a set of circRNAs, such an increase is due to the raised expression of the mA machinery, which we also find to control the proliferation activity of RMS cells. Furthermore, we identify the RNA helicase DDX5 as a mediator of the back-splicing reaction and as a co-factor of the mA regulatory network. DDX5 and the mA reader YTHDC1 are shown to interact and to promote the production of a common subset of circRNAs in RMS. In line with the observation that YTHDC1/DDX5 depletion reduces RMS proliferation, our results provide proteins and RNA candidates for the study of rhabdomyosarcoma tumorigenicity.
N6-甲基腺苷（mA）是众所周知的调控线性 RNA 代谢过程的关键因子。相反，它在环状 RNA（circRNA）的生物发生和功能中的作用还知之甚少。在这里，我们在横纹肌肉瘤（RMS）的病理环境中对 circRNA 的表达进行了表征，与野生型成肌细胞相比，发现其整体表达增加。对于一组 circRNAs，这种增加是由于 mA 机制的表达上调引起的，我们还发现它可以控制 RMS 细胞的增殖活性。此外，我们鉴定了 RNA 解旋酶 DDX5 作为反式剪接反应的介导因子，以及 mA 调控网络的辅助因子。DDX5 和 mA 阅读器 YTHDC1 被证明可以相互作用，并促进 RMS 中一组常见 circRNAs 的产生。与观察到的 YTHDC1/DDX5 耗竭减少 RMS 增殖一致，我们的结果为横纹肌肉瘤的致瘤性研究提供了蛋白质和 RNA 候选物。
