Binding of microRNAs (miRNAs) to mRNAs normally results in post-transcriptional repression of gene expression. However, extensive base-pairing between miRNAs and target RNAs can trigger miRNA degradation, a phenomenon called target RNA-directed miRNA degradation (TDMD). Here, we systematically analyzed Argonaute-CLASH (cross-linking, ligation, and sequencing of miRNA–target RNA hybrids) data and identified numerous candidate TDMD triggers, focusing on their ability to induce nontemplated nucleotide addition at the miRNA 3′ end. When exogenously expressed in various cell lines, eight triggers induce degradation of corresponding miRNAs. Both the TDMD base-pairing and surrounding sequences are essential for TDMD. CRISPR knockout of endogenous trigger or ZSWIM8, a ubiquitin ligase essential for TDMD, reduced miRNA degradation. Furthermore, degradation of miR-221 and miR-222 by a trigger in BCL2L11, which encodes a proapoptotic protein, enhances apoptosis. Therefore, we uncovered widespread TDMD triggers in target RNAs and demonstrated an example that could functionally cooperate with the encoded protein.

中文翻译：

---

目标 mRNA 中广泛存在的 microRNA 降解元件可以帮助编码的蛋白质

microRNA (miRNA) 与 mRNA 的结合通常会导致基因表达的转录后抑制。然而，miRNA 和靶 RNA 之间广泛的碱基配对会引发 miRNA 降解，这种现象称为靶 RNA 指导的 miRNA 降解 (TDMD)。在这里，我们系统地分析了 Argonaute-CLASH（miRNA-靶 RNA 杂交体的交联、连接和测序）数据，并确定了许多候选 TDMD 触发器，重点关注它们在 miRNA 3' 端诱导非模板化核苷酸添加的能力。当在各种细胞系中外源表达时，八种触发因素会诱导相应 miRNA 的降解。TDMD 碱基配对和周围序列对于 TDMD 都是必不可少的。CRISPR 敲除内源性触发器或 ZSWIM8（一种 TDMD 必需的泛素连接酶）减少了 miRNA 降解。此外，编码促凋亡蛋白的BCL2L11可增强细胞凋亡。因此，我们在目标 RNA 中发现了广泛的 TDMD 触发器，并展示了一个可以与编码的蛋白质在功能上合作的例子。