1 PhD project offered in the IPP winter call 2023/2024
We study the regulatory mechanisms that mediate DNA repair and contribute to ensuring the complete and accurate duplication of a cell’s genetic information in every cell cycle, especially in the face of DNA damage. We are particularly interested in the contributions of posttranslational protein modifiers of the ubiquitin family, such as ubiquitin and SUMO, to the regulation of genome maintenance pathways.
PhD Project: Manipulating the ubiquitin code
The ubiquitin system plays a key role in determining the function and fate of proteins in virtually every biological pathway, including genome maintenance and gene expression. Most often, ubiquitin signalling is mediated by polyubiquitin chains attached to selected substrate proteins. Depending on the linkage between the individual ubiquitin moieties, such chains can adopt many distinct forms and - by means of linkage-selective downstream effectors - convey distinct biological effects. In this manner, the ubiquitin system is implicated in a variety of genome maintenance pathways that protect us from diseases such as cancer, neurodegeneration and inflammation.
In our lab, we have developed tailor-made ubiquitylation enzymes that allow us to induce the polyubiquitylation of relevant cellular proteins in a controlled and linkage-selective manner. Here we will apply these tools to the investigation of ubiquitin signalling in selected biological contexts, including the processing of DNA polymerase-blocking lesions during DNA replication, the ubiquitin-dependent damage response pathway at DNA double-strand breaks, the contribution of ubiquitin to biological condensates via phase separation and the protection from pathological protein aggregates. The project will involve biochemical as well as cell and molecular biological approaches and aims to eluciate the relevance of ubiquitin signalling in cellular resilience mechanisms against ageing and disease.
If you are interested in this project, please select Ulrich as your group preference in the IPP application platform.
Publications relevant to this project
Yakoub G, Choi YS, Wong RP, Strauch T, Ann KJ, Cohen RE and Ulrich HD (2023) Avidity-based biosensors for ubiquitylated PCNA reveal choreography of DNA damage bypass. Science Adv, 9: eadf3041 Link
Shi J, Hauschulte K, Mikicic I, Maharjan S, Arz V, Strauch T, Heidelberger JB, Schaefer JV, Dreier B, Plückthun A, Beli P, Ulrich HD and Wollscheid HP (2023) Nuclear myosin VI maintains replication fork stability. Nat Commun 14:3787 Link
Wegmann S, Meister C, Renz C, Yakoub G, Wollscheid HP, Takahashi DT, Mikicic I, Beli P and Ulrich HD (2022) Linkage reprogramming by tailor-made E3s reveals polyubiquitin chain requirements in DNA-damage bypass. Mol Cell, 82:1589-1602 Link
Dr Helle D. Ulrich
Institute of Molecular Biology (IMB)
& Johannes Gutenberg University Mainz
D – 55128 Mainz