UPF1/SMG7-dependent microRNA-mediated gene regulation

Jungyun Park,Jin-Wu Nam,Jwa-Won Seo,Narae Ahn,Jungwook Hwang,Seokju Park

doi:10.1038/s41467-019-12123-7

Abstract

The stability and quality of metazoan mRNAs are under microRNA (miRNA)-mediated and nonsense-mediated control. Although UPF1, a core mediator of nonsense-mediated mRNA decay (NMD), mediates the decay of target mRNA in a 3′UTR-length-dependent manner, the detailed mechanism remains unclear. Here, we suggest that 3′UTR-length-dependent mRNA decay is not mediated by nonsense mRNAs but rather by miRNAs that downregulate target mRNAs via Ago-associated UPF1/SMG7. Global analyses of mRNAs in response to UPF1 RNA interference in miRNA-deficient cells reveal that 3′UTR-length-dependent mRNA decay by UPF1 requires canonical miRNA targeting. The destabilization of miRNA targets is accomplished by the combination of Ago2 and UPF1/SMG7, which may recruit the CCR4-NOT deadenylase complex. Indeed, loss of the SMG7-deadenylase complex interaction increases the levels of transcripts regulated by UPF1-SMG7. This UPF1/SMG7-dependent miRNA-mediated mRNA decay pathway may enable miRNA targeting to become more predictable and expand the miRNA-mRNA regulatory network.

Highlights

The stability and quality of metazoan messenger RNAs (mRNAs) are under microRNA-mediated and nonsense-mediated control
Early studies have reported that a considerable fraction of RNAs responsive to UPF1 depletion are dependent on the 3′untranslated regions (UTRs) length, the question of whether UPF1-responsive RNAs are degraded in an exon junction complex (EJC)-independent manner has repeatedly been asked
We examined changes in downstream exon junctions (dEJs)-free gene expression depending on their 3′UTR length using publicly available microarray data profiled from HeLa cells treated with siRNA for SMG5 or siRNA for SMG726. siSMG5 treatment did not affect expression of these genes (Supplementary Fig. 6d), whereas the results of siSMG7 resembled those of siRNA for UPF1 (siUPF1) (Fig. 6a)

Summary

Introduction

The stability and quality of metazoan mRNAs are under microRNA (miRNA)-mediated and nonsense-mediated control. Loss of the SMG7-deadenylase complex interaction increases the levels of transcripts regulated by UPF1-SMG7 This UPF1/SMG7-dependent miRNA-mediated mRNA decay pathway may enable miRNA targeting to become more predictable and expand the miRNA-mRNA regulatory network. Globally progressive lengthening of 3′UTRs is observed during brain development[13], and extended 3′UTRs embed thousands of conserved MREs in mammals[10], strengthening miRNA-mediated gene regulation[14] In addition to these cis-acting element-specific mechanisms, lengthening of the 3′UTR may influence the stability of mRNAs through the nonsense-mediated mRNA decay (NMD) pathway[15]

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Results

Conclusion