Eukaryotes have evolved a variety of mRNA surveillance mechanisms to detect and degrade aberrant mRNAs with potential deleterious outcomes. Among them, nonsense-mediated mRNA decay (NMD) functions not only as a quality control mechanism targeting aberrant mRNAs containing a premature termination codon (PTC), but also as a post-transcriptional gene regulation mechanism targeting numerous physiological mRNAs. Despite its well-characterized molecular basis, the regulatory scope and biological functions of NMD at an organismal level are incompletely understood. In humans, mutations in genes encoding core NMD factors cause specific developmental and neurological syndromes, suggesting a critical role of NMD in the central nervous system. Here, we review the accumulating biochemical and genetic evidence on the developmental regulation and physiological functions of NMD, as well as an emerging role of NMD dysregulation in neurodegenerative diseases.
Expansion of short tandem repeats (STRs) in the human genome underlies over fifty genetic disorders. A common pathological feature of repeat RNAs is their propensity to aggregate in cells. While these RNA aggregates have been shown to cause toxicity by sequestering RNA-binding proteins, the molecular mechanism of repeat RNA aggregation remains unclear. Here we devised a generalizable method to efficiently generate long tandem repeat DNAs de novo and applied it to systematically determine the sequence features underlying RNA aggregation. Live-cell imaging of repeat RNAs indicated that aggregation was mainly driven by multivalent RNA-RNA interactions via either canonical or noncanonical base pairs. While multiple short runs of two consecutive base pairs were sufficient, longer runs of consecutive base pairs such as those formed by a neurodegeneration-associated hexanucleotide repeat further enhanced aggregation. In summary, our study provides a unifying model for the molecular basis of repeat RNA aggregation and a generalizable approach for identifying the sequence and structural determinants of repeat RNA properties.
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