Circular RNAs (circRNAs) represent an abundant and conserved entity of non-coding RNAs; however, the principles of biogenesis are currently not fully understood. Here, we identify two factors, splicing factor proline/glutamine rich (SFPQ) and non-POU domain-containing octamer-binding protein (NONO), to be enriched around circRNA loci. We observe a subclass of circRNAs, coined DALI circRNAs, with distal inverted Alu elements and long flanking introns to be highly deregulated upon SFPQ knockdown. Moreover, SFPQ depletion leads to increased intron retention with concomitant induction of cryptic splicing, premature transcription termination, and polyadenylation, particularly prevalent for long introns. Aberrant splicing in the upstream and downstream regions of circRNA producing exons are critical for shaping the circRNAome, and specifically, we identify missplicing in the immediate upstream region to be a conserved driver of circRNA biogenesis. Collectively, our data show that SFPQ plays an important role in maintaining intron integrity by ensuring accurate splicing of long introns, and disclose novel features governing Alu-independent circRNA production.

中文翻译：

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RNA 结合蛋白 SFPQ 保留长内含子剪接并调节哺乳动物中的 circRNA 生物合成


环状 RNA (circRNA) 代表丰富且保守的非编码 RNA 实体；然而，生物发生的原理目前尚未完全了解。在这里，我们确定了两个因子，富含脯氨酸/谷氨酰胺的剪接因子（SFPQ）和不含 POU 结构域的八聚体结合蛋白（NONO），它们在 circRNA 位点周围富集。我们观察到 circRNA 的一个亚类，即 DALI circRNA，其远端倒置 Alu 元件和长侧翼内含子在 SFPQ 敲低后高度失调。此外，SFPQ 耗尽导致内含子保留增加，同时诱导隐秘剪接、过早转录终止和聚腺苷酸化，特别是长内含子时普遍存在。产生 circRNA 的外显子上游和下游区域的异常剪接对于形成 circRNAome 至关重要，具体而言，我们发现直接上游区域的错误剪接是 circRNA 生物发生的保守驱动因素。总的来说，我们的数据表明，SFPQ 通过确保长内含子的准确剪接在维持内含子完整性方面发挥着重要作用，并揭示了控制不依赖于 Alu 的 circRNA 生产的新特征。