We want to create a strong and dynamic crosstalk between basic research in RNA metabolism and translational applications in RNA therapeutics.
Concerning basic research, we pursue our investigations on the mechanisms of co-transcriptional mRNP biogenesis and quality control (QC) in yeast and mammalian cells using our Rho-based approach as a tool. We perform transcriptomics (ChIP-Seq and RNA-Seq) and proteomics (mRNPs pulldown and protein maps by mass spec) to explore the interplay between the two mRNP QC and degradation pathways that we discovered previously. This should provide valuable information regarding specialized QC pathways and corresponding subsets of transcripts. Another aspect involves the characterization of the aberrancies induced by Rho during mRNP biogenesis such as the removal of specific mRNA processing and binding proteins which are required for mRNP assembly and export. Such characterization will likely reveal the specific features that distinguish normal mRNA assembled into mRNPs and exported into the cytoplasm for translation from noncoding RNAs (antisense and intergenic RNAs) which are highly unstable although they possess a cap structure and a polyA tail as mRNA. We hope to significantly contribute to the growing field of noncoding RNAs as actors in gene regulation at the level of transcription, mRNA decay and translation. Last, we plan to understand the role of Rna15 in the QC process. Rna15 is a part of the highly conserved termination and polyadenylation complex (Rna14-Rna15-Clp1-Pcf11) recruited mostly at the end of the genes and recently co-localized along a subset of transcripts with the QC complex Nrd1-Nab3. In parallel, we search for an improved antimicrobial activity of new molecules using our Rho-based screen in yeast.
These last years, we are witnessing the emergence of RNA based biopharmaceuticals as a new class of treatment and prophylactic for chronic and rare diseases, including cancer. RNA based-therapeutics are more promising than DNA therapeutics. It is now admitted that for RNA therapeutics clinical translation, a special care must be taken to improve their production, stability and cellular delivery.
In the project “Biomédicaments” we intend to set up a new technology to produce large amounts of vaccine-grade mRNAs in yeast. We search to improve the biological activity of mRNA based-therapeutics by studying the intracellular fate of exogenous RNA.
- Mosrin-Huaman C., Hervouet-Coste N. and Rahmouni A. R. Co-transcriptional degradation by the 5'-3' exonuclease Rat1p mediates quality control of HXK1 mRNP biogenesis in S. cerevisiae. (2016) RNA Biol. 13, 582–592.
Stuparevic I., Mosrin-Huaman C., Hervouet-Coste N., Remenaric M. and Rahmouni A. R. Co-transcriptional Recruitment of RNA Exosome Cofactors Rrp47p and Mpp6p and Two Distinct TRAMP Complexes Assists the Exonuclease Rrp6p in the Targeting and Degradation of an Aberrant mRNP in Yeast (2013) J. Biol. Chem. 288, 31816-31829.
Honorine R., Mosrin-Huaman C., Hervouet-Coste N., Libri D. and Rahmouni A. R. Nuclear mRNA quality control in yeast is mediated by Nrd1 co-transcriptional recruitment (2011) Nucleic Acids Res. 39, 2809-2820.
Proshkin S., Rahmouni A. R., Mironov A. and Nudler E. Cooperation between Translating Ribosomes and RNA Polymerase in Transcription Elongation. (2010) Science. 328, 504-508.