Research
Nuclear RNA surveillance and post-transcriptional gene regulation
Protein-coding genes occupy just a few percent of the three billion basepairs that make up our chromosomes. Yet, a large portion of eukaryotic genomes is transcribed into RNA. In healthy cells, RNA produced by this pervasive transcription of the genome does not accumulate because it is targeted by nuclear RNA surveillance pathways and is highly unstable. Although such “cryptic” transcripts share many features with functional messenger RNAs (for example, they can be both capped and polyadenylated – two RNA modifications originally considered to be hallmarks of protein-coding transcripts), cells clearly differentiate between spurious and bona fide transcripts and consign them to different fates.
The key factor responsible for the rapid destruction of cryptic transcripts in the nucleus is the nuclear RNA exosome, a conserved ribonucleolytic multi-protein complex with a central role in RNA quality control (Kilchert et al., Nat Rev Mol Cell Biol., 2016; Kilchert, Methods Mol Biol., 2020). Its exonuclease DIS3 is frequently mutated in multiple myeloma and associated with poor prognosis. The exosome removes products of cryptic transcription, controls levels of non-coding RNAs, suppresses transposable elements, and mediates post-transcriptional gene silencing of heterochromatin and developmental genes. In addition, it targets aberrant transcripts that were incorrectly processed. In my lab, we are interested in the mechanisms at the heart of this molecular triage.
Mission
In our opinion, the key to understanding early fate determination of RNAs are RNA-binding proteins. Nascent RNAs are immediately coated with proteins that guide RNA processing and ultimately control all aspects of the RNA life cycle. As the RNA matures, the ribonucleoprotein complex (RNP) it is part of is constantly remodelled. In many cases, RNA processing failure leads to retention at the site of transcription and RNA decay, suggesting that there are quality control checkpoints in early RNP assembly. However, how cells monitor essential processing events and signal checkpoint completion once an RNP can be licensed for export – and how this information is encoded in the RNP coat – is still only partly understood. To further our understanding of these processes, my lab focusses on different aspects of early post-transcriptional control:
- Positive regulation of exosome-dependent RNA decay through RNA-binding exosome specificity factors.
- Escape from exosome-dependent RNA decay through RNP remodelling by DEAD-box ATPases.
- Feed-back mechanisms that signal the local activation of the nuclear RNA surveillance machinery back to the transcribed chromatin.