Complex industrial manufacturing processes require multiple quality control checks along the assembly line to ensure a high proportion of correctly assembled, properly functioning final products. Similarly, multiple quality control systems have evolved to recognize mistakes in the intricate chain of complicated biochemical reactions that are involved in the correct expression of the genetic information in each of our cells. Among those, “nonsense-mediated mRNA decay” (NMD) represents a translation-coupled quality control mechanism that recognizes and rapidly degrades mRNAs of which the protein coding sequence is truncated by the presence of a premature termination codon (PTC). By eliminating these defective, so-called nonsense mRNAs with crippled protein-coding capacity, NMD substantially reduces the synthesis of potentially deleterious truncated proteins in the cell. Given that about 30% of all known disease-causing mutations in humans lead to the production of a nonsense mRNA, NMD serves as an important modulator of the clinical manifestations of genetic diseases, and manipulating NMD therefore represents a promising strategy for future therapies of many genetic disorders. Despite 30 years of intensive research, our understanding of the underlying molecular mechanisms of NMD is still fragmented.

A main goal of our research is to understand at the molecular level how PTCs are recognized and distinguished from correct termination codons and how this recognition of nonsense mRNAs subsequently triggers their rapid degradation. Since NMD is tightly coupled to translation termination, we began to investigate the process of translation termination on NMD sensitive and NMD insensitive mRNAs to gain insights into the mechanism of PTC recognition and NMD activation. We employ both, biochemical in vitro approaches and in vivo (i.e. in cultured human cells) assays to address these questions, including state-of-the art next generation sequencing and proteomics.