MicroRNA Serves as an mRNA Surveillance System to Eliminate Nonsense Messages

Numerous studies have established important roles for micoRNAs (miRNAs) in gene expression regulation since their discovery two decades ago. A novel role for miRNAs in mRNA quality control has been discovered recently by researchers from Dr. WU Ligang’s lab of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences.

Eukaryotic cells are constantly at risk for various types of mutations, among which the nonsense mutation is a severe type that converts a coding codon into a stop codon, leading to the premature termination of translation and the expression of proteins truncated at the carboxyl terminus. These truncated protein products often have deleterious dominant-negative or gain-of-function effects that interfere with normal biological processes in cells. One well-known mechanism for recognizing premature termination codon (PTC)-containing transcripts is exon-exon junction complex (EJC)-dependent NMD (EJC-NMD). However, not all nonsense mRNAs can be recognized and degraded by EJC-NMD, such as APC, a critical tumor suppressor gene that relates to colorectal cancer. miRNA is a class of small noncoding RNA that post-transcriptionally regulates gene expression by imperfectly base-pairing with its responsive elements (miRE) located in the 3’ unstranslated regions (3’ UTR) of mRNAs. Upon recognition of the PTC by the translating ribosome, the downstream portion of the coding region of an mRNA is redefined as part of the 3’ UTR; as a result, the miREs embedded in this region can be detected by miRNAs, triggering miRNA-mediated repression of this mRNA.

ZHAO Ya and colleagues demonstrated that miRNA is able to selectively target and repress the expression of nonsense mRNAs by both expedited poly(A) tail removal and translational repression, a mechanism they named miRNA-mediated surveillance. They provided evidences that naturally occurring cancer-causing nonsense mRNAs---including APC, are repressed by miRNA-mediated surveillance. They further showed that this mechanism works independently of the EJC-NMD; however, both mechanisms can work in parallel alongside each other, which provides extra protection against nonsense mutations. These observations reveal a new function of miRNA and provide a potential approach to repress deleterious nonsense transcripts without impairing their wild-type counterparts for the treatment of diseases caused by nonsense mutations.

The study entitled “MicroRNA-mediated repression of nonsense mRNAs” was published online in eLife on August 8, 2014. This work was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and Chinese Academy of Sciences.

Model of miRNA mediated surveillance to repress nonsense mutant. The coding region of an mRNA may contain multiple potential miREs. Usually, miRNAs cannot stably bind to their cognate miREs that are embedded within the ORF of a normal transcript under active translation (left). However, upon nonsense mutation, the translating ribosome stalls at the PTC so that miREs downstream of the PTC are unmasked, triggering miRNA-mediated deadenylation and translational repression. (Image provided by Prof. Wu Ligang`s group)