Normal & Disease-Associated RNA Decay
The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex.
In mammalian cells, the pioneer translation initiation complex structurally overlaps with the steady-state translation initiation complex but is functionally distinct. The pioneer translation initiation complex supports the pioneer round of translation. This complex is the primary target of nonsense-mediated mRNA decay (NMD), which is a quality-control pathway (also called an mRNA-surveillance pathway). In contrast, the steady-state translation initiation complex supports the bulk of cellular protein synthesis and is the primary target of pathways that conditionally regulate gene expression.
Half of the research in my lab focuses on NMD, which likely evolved to safeguard cells from potentially deleterious proteins produced as a consequence of routine mistakes in gene expression. In mammalian cells, these mistakes include inaccuracies in transcription initiation or pre-mRNA splicing, and ineffective somatic DNA rearrangements of the type that characterize the immunoglobulin and T-cell receptor genes. These mistakes often result in mRNAs having reading frames upstream of the usual reading frame, frameshift mutations that generate nonsense codons, or nonsense mutations. NMD also down-regulates a number of naturally occurring transcripts, including some selenoprotein mRNAs and alternatively spliced RNAs.
The other half of our research focuses on a mechanistically related pathway called Staufen1(STAU1)-mediated mRNA decay (SMD). SMD degrades mRNAs that harbor a binding site for the double-stranded RNA-binding protein STAU1 in their 3'-untranslated regions (3'UTRs). Remarkably, depending on the particular mRNA, STAU1-binding sites (SBSs) can be formed by either intramolecular base-pairing within a 3'UTR or by intermolecular base-pairing between an mRNA 3'UTR and a long non-coding RNA (lnchRNAs) as a means to conditionally regulate gene expression. Like microRNAs, more than one lncRNA can target a single mRNA, and a single lncRNA can target more than one mRNA.
- Staufen-mediated mRNA decay. Wiley Interdiscip Rev RNA. In press. (2013 May 16).
- Control of myogenesis by rodent SINE-containing lncRNAs. Genes Dev. 27, 793-804. (2013 Apr 01).
- Staufen1 dimerizes through a conserved motif and a degenerate dsRNA-binding domain to promote mRNA decay. Nat Struct Mol Biol. 20, 515-24. (2013 Apr 01).