Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Bioinformatics and Computational Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nucleic Acids Res. 2020 Jul 27;48(13):7468-7482. doi: 10.1093/nar/gkaa491.
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.
可变多聚腺苷酸化 (APA) 产生具有不同序列、长度、稳定性和功能的转录本 3'非翻译区 (3'UTR)。我们在这里表明，APA 产物包括一类隐秘的无义介导的 mRNA 降解 (NMD) 底物，它们具有延伸的 3'UTR，而 NMD 的基因或转录水平分析往往无法检测到这些底物。在转录组范围内，核心 NMD 因子 UPF1 优先识别 APA 的长 3'UTR 产物，导致它们的系统下调。与这种机制相反，多功能 RNA 结合蛋白 PTBP1 通过抑制 NMD 来调节短和长 3'UTR 亚型的平衡，除了其先前描述的对共转录多聚腺苷酸化 (polyA) 位点选择的调节。此外，我们发现许多在多种肿瘤类型中改变 APA 亚型丰度的转录本受 NMD 控制。总之，我们的发现揭示了 NMD 在塑造 APA 结果方面的广泛作用。
