Projects Offered

1 PhD project offered in the IPP summer call Molecular Mechanisms in Genome Stability & Gene Regulation

Scientific Background

Nuclear mRNA export is an essential step in eukaryotic gene expression, ensuring that mature transcripts are delivered from the nucleus to the cytoplasm for translation. Multiple challenges are faced in this process: How are mRNAs discriminated against all other nuclear RNAs? How does the cell ensure that only fully matured mRNAs are exported? How are faulty mRNAs and transcription byproducts targeted for degradation? At the core of mRNA nuclear export works an evolutionary conserved machinery centered on a large protein complex: TREX. While we recently uncovered a mechanistic framework of the core of this pathway, the regulatory layers, connections to diverse cellular processes and repurposing for the export of non-canonical mRNAs remains cryptic. 

PhD Project: Mechanistic insights into novel mRNA export complexes

During transcription each Polymerase II transcript engages with various RNA binding proteins to form a ribonucleoprotein complex (mRNP). A key player is the TREX complex, consisting of the DExD-box ATPase UAP56 and the THO complex, which is crucial to aid co-transcriptional mRNP packaging. Failure to engage TREX leads to entanglement of the nascent RNA with DNA, producing R-loops and resulting in genome instability. Intriguingly, TREX can only be recruited to an mRNA through UAP56. We previously discovered multiple novel direct interactors of UAP56, however their specific function is unclear. 

Using a combination of biochemical reconstitution, biophysical characterization and structural biology (including AlphaFold predictions and cryo-Electron Microscopy), we will investigate the formation of novel mRNP packaging complexes. Applying cellular assays (endogenous CRISPR-tagging, reporter systems, RNA-FISH), proteomics, transcriptomics and high-resolution microscopy we will further dissect the co-transcriptional recruitment of the packaging and export machinery to nascent RNAs. By integrating molecular biology, genetics, and biophysical approaches, we aim to obtain new mechanistic insights into the co-transcriptional packaging of mRNPs, a central aspect of nuclear gene expression.

This project will be part of the RTG on R-loop Regulation in Robustness and Resilience (4R).

If you are interested in this project, please select Hohmann as your group preference in the IPP application platform.

Publications relevant to this project 

Hohmann U, Graf M, Schellhaas U, Pacheco-Fiallos B, Fin L, Riabov-Bassat D, Pühringer T, Szalay MF, Tirian L, Handler D, Brennecke J, Plaschka C (2026) An ATP-gated molecular switch orchestrates human mRNA export. Nature. 649, 1042-1050 Link

Pühringer T*, Hohmann U*, Fin L, Pacheco-Fiallos B, Schellhaas U, Brennecke J, Plaschka C (2020) Structure of the human core transcription-export complex reveals a hub for multivalent interactions. eLife. 9, e61503 Link * indicates equal contribution