Abstract
Nonsense-mediated decay (NMD) plays a fundamental role in the degradation of premature termination codon (PTC)-containing transcripts, but also regulates the expression of functional transcripts lacking PTCs, although such ‘non-canonical’ functions remain ill-defined and require the identification of factors targeting specific mRNAs to the NMD machinery. Our work identifies the stem cell-specific mRNA repressor protein TRIM71 as one of these factors. TRIM71 plays an essential role in embryonic development and is linked to carcinogenesis. For instance, TRIM71 has been correlated with advanced stages and poor prognosis in hepatocellular carcinoma. Our data shows that TRIM71 represses the mRNA of the cell cycle inhibitor and tumor suppressor CDKN1A/p21 and promotes the proliferation of HepG2 tumor cells. CDKN1A specific recognition involves the direct interaction of TRIM71 NHL domain with a structural RNA stem-loop motif within the CDKN1A 3′UTR. Importantly, CDKN1A repression occurs independently of miRNA-mediated silencing. Instead, the NMD factors SMG1, UPF1 and SMG7 assist TRIM71-mediated degradation of CDKN1A mRNA, among other targets. Our data sheds light on TRIM71-mediated target recognition and repression mechanisms and uncovers a role for this stem cell-specific factor and oncogene in non-canonical NMD, revealing the existence of a novel mRNA surveillance mechanism which we have termed the TRIM71/NMD axis.
Highlights
Nonsense-mediated decay (NMD) is an important RNA surveillance pathway well known to control the degradation of transcripts harboring premature termination codons (PTC) [1,2]
The strong TRIM71 expression observed in patients with advanced-stage hepatocellular carcinoma (HCC) negatively correlates with CDKN1A mRNA expression, while it positively correlates with AGO2 expression (Supplementary Figure S2B)
TRIM71 represses CDKN1A expression via 3 UTR recognition followed by mRNA degradation, and promotes cancer cell proliferation
Summary
Nonsense-mediated decay (NMD) is an important RNA surveillance pathway well known to control the degradation of transcripts harboring premature termination codons (PTC) [1,2]. Induction of NMD for a particular transcript is linked to the interpretation of a premature translation termination [7], and discerning between a PTC and the normal stop codon is crucial for eliciting canonical NMD. When the ribosome stalls at a PTC, the major NMD effector UPF1 together with its activating kinase SMG1 are recruited through their binding to the release factors eRF1 and eRF3 to form the surveillance complex (SURF). The SURF complex interacts with other NMD effectors present in the EJC – UPF2 and UPF3b – to form the decay-inducing complex (DECID), resulting in SMG1 activation and UPF1 phosphorylation. Phosphorylated UPF1 recruits both the endonuclease SMG6, which cleaves the RNA in the vicinity of the PTC, and the dimer SMG5–SMG7, which triggers CCR4–
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