Projects Offered

1 PhD project offered in the IPP winter call 2026/2027

Scientific background

R-loops occur naturally during transcription and can have important regulatory functions, however, persistence of R-loops can have deleterious effects and result in the accumulation of DNA double-strand breaks and genome instability. DNA damage and aberrant R-loops have been linked to human diseases, including neurodegenerative disorders. For instance, several genes that are mutated in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have been implicated in DNA damage repair and the regulation of R-loops, suggesting that DNA damage and genome instability may contribute to neurodegeneration in these disorders. Two of these ALS/FTD-associated genes encode for the major aggregating proteins in ALS and FTD patients, TAR DNA binding protein of 43 kDa (TDP-43) and Fused in Sarcoma (FUS). They are ubiquitously expressed DNA/RNA-binding proteins that are normally predominantly localized in the nucleus. However, in the degenerating brain regions of ALS and FTD patients, TDP-43 and FUS are largely absent from the nucleus and accumulate in cytosolic aggregates of neurons and glial cells, resulting in a loss of nuclear TDP-43 or FUS function. TDP-43 or FUS depletion by RNA interference causes DNA damage and R-loop accumulation and DNA damage markers are elevated in brains of ALS/FTD patients. The molecular mechanisms by which TDP-43 and FUS contribute to DNA repair and suppress R-loops are largely unknown.

PhD project: Role of FUS and TDP-43 in R-loop regulation and genome stability

This project seeks to unravel the molecular mechanisms by which FUS and TDP-43 contribute to R-loop suppression and DNA repair, using a combination of in vitro and cellular model systems. Questions that we would like to address include:

1. How does the protein interactome of FUS and TDP-43 get rewired upon DNA damage?
2. Is their phase separation/condensation behavior or their ability to bind to DNA/RNA required for R-loop suppression or their recruitment to damage sites?
3. How do post-translational modifications, e.g. ADP-ribosylation and phosphorylation, regulate FUS or TDP-43’s function in R-loop suppression and the DNA damage response?
4. Where in the genome do R-loops appear upon FUS or TDP-43 loss-of-function?

The project involves a wide methods spectrum, ranging from proximity proteomics, over molecular cell biology (advance fluorescence microscopy, live cell imaging) to protein biochemistry (in vitro assays with recombinant proteins) and the possibility to learn and apply genome-wide R-loop mapping techniques.

This project will be part of the RTG on R-loop Regulation in Robustness and Resilience (4R). More information can be found at: Project 6. R-loop regulation by neurodegeneration-linked DNA/RNA-binding proteins FUS and TDP-43. - 4R-RTG

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

Publications relevant to the project

Zadorozhna Y*, Uliana F*, Zippo E, Busch A, Kretschmer N, Mosna S, Suk Y, Chen J, Schmidt C, Stelzl LS, Dormann D (2026) Phase separation behavior of TDP-43 governs its protein interactome and regulation of alternative splicing. BioRxiv 2026.04.06.716630 Link

Simonetti F, Zhong W, Hutten S, Uliana F, Schifferer M, Rezaei A, Ramirez LM, Hochmair J, Sankar R, Gopalan A, Kielisch F, Riemenschneider H, Ruf V, Schmidt C, Simons M, Zweckstetter M, Wegmann S, Lashley T, Polymenidou M, Edbauer D#, Dormann D# (2025) Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding. EMBO J. 44(24):7395-7433 Link

Gruijs da Silva LA, Simonetti F, Hutten S, Riemenschneider H, Sternburg EL, Pietrek LM, Gebel J, Dötsch V, Edbauer D, Hummer G, Stelzl LS and Dormann D (2022) Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. EMBO J, 41:e108443 Link

Alberti S, Dormann D. (2019) Liquid-Liquid Phase Separation in Disease. Annu Rev Genet. Dec 3;53:171-194. Link

Hofweber D*, Hutten S*, Bourgeois B, Spreitzer E, Niedner-Boblenz A, Schifferer M, Ruepp MD, Simons M, Niessing D, Madl T, Dormann D# (2018). Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173(3):706-719.e13 Link