Nonsense-mediated mRNA decay: terminating erroneous gene expression

Nonsense-mediated mRNA decay is a surveillance pathway that reduces errors in gene expression by eliminating aberrant mRNAs that encode incomplete polypeptides. Recent experiments suggest a working model whereby premature and normal translation termination events are distinct as a consequence of the spatial relationship between the termination codon and mRNA binding proteins, a relationship partially established by nuclear pre-mRNA processing. Aberrant termination then leads to both translational repression and an increased susceptibility of the mRNA to multiple ribonucleases.     

Synergy between transcription and mRNA processing events

Processing of eukaryotic pre-mRNAs is an important step for the translation of proteins. These processing events include the addition of a cap structure at the 5' terminus of the pre-mRNA, the splicing out of introns and the acquisition of a polyadenosine tail at the 3' terminus of the pre-mRNA. It has now become apparent that the RNA processing events can significantly influence each other. RNA polymerase II appears as a key player in these processes, cooperating with numerous processing factors that are involved in capping, splicing, and polyadenylation. More specifically, the carboxyterminal domain of the large subunit of the enzyme plays a critical role in coordination of the processing events. The number of interactions between the various RNA processing events identified so far reflects the complexity of these reactions. As more studies focus on these interactions, additional links and cellular partners will undoubtedly be discovered.     

Autogenous regulation of histone mRNA decay by histone proteins in a cell-free system.

We tested the hypothesis that histone mRNA turnover is accelerated in the presence of free histone proteins. In an in vitro mRNA decay system, histone mRNA was degraded four- to sixfold faster in reaction mixtures containing core histones and a cytoplasmic S130 fraction than in reaction mixtures lacking these components. The decay rate did not change significantly when histones or S130 was added separately, suggesting either that the histones were modified and thereby activated by S130 or that additional factors besides histones were required. RecA, SSB (single-stranded binding), and histone proteins all formed complexes with histone mRNA, but only histones induced accelerated histone mRNA turnover. Therefore, the effect was not the result of random RNA-protein interactions. Moreover, histone proteins did not induce increased degradation of gamma globin mRNA, c-myc mRNA, or total poly(A)- or poly(A)+ polysomal mRNAs. This autoregulatory mechanism is consistent with the observed accumulation of cytoplasmic histone proteins in cells after DNA synthesis stops, and it can account, in part, for the rapid disappearance of histone mRNA at the end of S phase.     

Mechanisms of DNA-binding specificity and functional gene regulation by transcription factors

1. Download : Download high-res image (155KB)
2. Download : Download full-size image