PDF(Pubmed)
Abstract：
RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.
摘要：
RNA剪接是转录后基因调控的关键,然而，人类内含子长度的指数扩展对精确剪接提出了挑战。这里,我们确定hnRNPM是一种必需的RNA结合蛋白，通过与深层内含子结合来抑制隐蔽剪接，保持人类转录组的完整性。内含子中长散布的核元素（LINE）具有许多伪剪接位点。hnRNPM优先结合内含子LINE，以抑制假剪接位点用于隐蔽剪接。值得注意的是,隐蔽外显子可以通过散布在LINE中的反向ALU转座因子的碱基配对产生长dsRNA，从而引发干扰素反应。众所周知的抗病毒防御机制。重要的是,hnRNPM缺陷型肿瘤显示干扰素相关途径上调和免疫细胞浸润升高。这些发现揭示了hnRNPM作为转录组完整性的守护者，通过抑制隐蔽剪接，并表明靶向肿瘤中的hnRNPM可用于触发炎症免疫反应。从而加强癌症监测。
