MicroRNA 125 represses nonsense-mediated mRNA decay by regulating SMG1 expression

• miRNA-125 is a bona fide negative regulator of SMG1 in humans.
• miR-125 binds to a MRE in 3′ UTR of SMG1 mRNA and leads to its degradation.
• miR-125 suppresses the NMD pathway by repressing the levels of SMG1 protein.
• We suggest the existence of an RNA circuit linking the microRNA and NMD pathways.

Nonsense-mediated mRNA decay (NMD) is a cellular response mechanism that eliminates aberrant mRNA transcripts and thereby prevents the production of potentially deleterious C-terminally truncated proteins. The phosphatidylinositol 3-kinase-related protein kinase SMG1 is considered to be an essential factor in the NMD pathway. We demonstrate that the brain-enriched microRNA, miRNA-125 (miRNA-125a and miRNA-125b) is a bona fide negative regulator of SMG1 in humans. Down-regulation of SMG1 expression is mediated by miRNA-125 binding to a microRNA response element in the 3′ untranslated region of SMG1 mRNA, which leads to degradation of the SMG1 mRNA. In human cells, overexpression of miR-125 represses the endogenous levels of SMG1 protein and suppresses the NMD pathway; however, knockdown of miR-125 up-regulates the NMD pathway. These results suggest the existence of an RNA circuit linking the microRNA and NMD pathways.