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.

All metazoan mRNAs have a poly(A) tail at the 3′ end with the exception of replication‐dependent histone (RDH) mRNAs, which end in a highly conserved stem‐loop (SL) structure. However, a subset of RDH mRNAs are reported to be polyadenylated under physiologic conditions. The molecular details of the biogenesis of polyadenylated RDH [poly(A)+ RDH] mRNAs remain unknown. In this study, our genome‐wide analyses reveal that puromycin treatment or UVC irradiation stabilizes poly(A)+ RDH mRNAs, relative to canonical RDH mRNAs, which end in an SL structure. We demonstrate that the stabilization of poly(A)+ RDH mRNAs occurs in a translation‐independent manner and is regulated via human antigen R (HuR) binding to the extended 3′ UTR under stress conditions. Our data suggest that HuR regulates the expression of poly(A)+ RDH mRNAs.—Ryu, I., Park, Y., Seo, J.‐W., Park, O. H., Ha, H., Nam, J.‐W., Kim, Y. K. HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions. FASEB J. 33, 2680–2693 (2019). http://www.fasebj.org