Activation and inhibition of nonsense-mediated mRNA decay control the abundance of alternative polyadenylation products
Activation and inhibition of nonsense-mediated mRNA decay control the abundance of alternative polyadenylation products
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DOI：
10.1093/nar/gkaa491
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发表时间：
2020-07-27
影响因子：
14.9
通讯作者：
Hogg, J. Robert
中科院分区：
文献类型：
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作者：
Kishor, Aparna;Fritz, Sarah E.;Hogg, J. Robert
选择性聚腺苷酸化（阿帕）产生具有不同序列、长度、稳定性和功能的转录物3'非翻译区（3'UTR）。我们在这里表明，阿帕产品包括一类神秘的无义介导的mRNA衰变（NMD）基板与延长的3'UTR，基因或转录水平的分析NMD往往无法检测。在转录组范围内，核心NMD因子UPF 1优先识别阿帕的长3'UTR产物，导致其系统性下调。抵消这种机制，多功能RNA结合蛋白PTBP 1调节短和长的3'UTR亚型的平衡，通过抑制NMD，除了其先前描述的共转录多聚腺苷酸化（polyA）位点选择的调节。此外，我们发现，许多转录本与改变阿帕异构体丰度在多种肿瘤类型的NMD控制。总之，我们的研究结果揭示了NMD在塑造阿帕结果中的广泛作用。
Alternative polyadenylation (APA) produces transcript 3' untranslated regions (3'UTRs) with distinct sequences, lengths, stabilities and functions. We show here that APA products include a class of cryptic nonsense-mediated mRNA decay (NMD) substrates with extended 3'UTRs that gene- or transcript-level analyses of NMD often fail to detect. Transcriptome-wide, the core NMD factor UPF1 preferentially recognizes long 3'UTR products of APA, leading to their systematic downregulation. Counteracting this mechanism, the multifunctional RNA-binding protein PTBP1 regulates the balance of short and long 3'UTR isoforms by inhibiting NMD, in addition to its previously described modulation of co-transcriptional polyadenylation (polyA) site choice. Further, we find that many transcripts with altered APA isoform abundance across multiple tumor types are controlled by NMD. Together, our findings reveal a widespread role for NMD in shaping the outcomes of APA.