UPF1/SMG7-dependent microRNA-mediated gene regulation

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.

Nonsense‐mediated decay factor SMG7 sensitizes cells to TNFα‐induced apoptosis via CYLD tumor suppressor and the noncoding oncogene Pvt1

“…Whether SMG7 targets these transcripts on its own or in concert with other NMD proteins remains to be determined. SMG7 alone may contain the capacity to degrade RNA transcripts via interaction with CNOT8 [11] and can also degrade 3′ UTR length‐dependent mRNA via UPF1/SMG7‐dependent miRNA‐mediated mRNA decay pathway [48]. Screening results of other NMD factors, in contrast to Smg7 , did not reveal protection against TNFα (Fig.…”

UPF1-Mediated RNA Decay—Danse Macabre in a Cloud

“…A considerable proportion of CUG motifs were embedded in miRNA 7mer sites of abundant miRNA families and such miRNA target mRNAs were significantly upregulated in UPF1-depleted cells. This effect disappeared when the CUG motif was mutated and upon depletion or deletion of Dicer, suggesting a correlation between miRNA- and UPF1-mediated decay [ 200 ]. UPF1 and AGO binding sites have previously been shown to overlap [ 124 ].…”

“…SMG7 is recruited by UPF1 to a complex that also contains AGO and interacts with deadenylase complex components NOT1 and NOT3 in a SMG7 dependent manner. However, other than in the canonical miRNA pathway, GW182 (also known as TNRC6A/C) is not required for the interaction with the CCR4/NOT complex, indicating that UPF1/SMG7-dependent miRNA-mediated gene regulation may constitute an alternative miRNA targeting pathway [ 200 ]. UPF1/SMG7/miRNA-mediated mRNA decay has been dubbed UPF1-mediated decay (UMD) by its discoverers who posit that this decay pathway, rather than NMD, is the norm for EJC-independent degradation of mRNAs with long 3′UTRs and degrades between 40% and 50% of all error-free NMD substrates [ 200 ].…”

“…Upon proinflammatory stimuli or in cells and tissues involved in the immune response PTGS2 may be a target of RMD rather than NMD. Similarly, the PEA15 transcript has been assigned both to NMD [ 214 ] and UPF1/SMG7/miRNA-MD [ 200 ]. PEA15, like PTGS2 mRNA, contains both a long 3′UTR and a uORF and therefore can likely be degraded by both pathways, either simultaneously or exclusively, depending on cell type, physiological situations, timing or subcellular location.…”

HNRNPD interacts with ZHX2 regulating the vasculogenic mimicry formation of glioma cells via linc00707/miR-651-3p/SP2 axis

“…miRNA is a type of noncoding RNA with regulatory functions in eukaryotes. It is ~20–25 nt in length and can specifically bind to the 3′ untranslated region (3′UTR) of the target genes in order to regulate their expressions 18 . Studies have shown that miR-651-3p negatively regulates TIAM1, which is highly expressed in gastric cancer cells 19 .…”