1 PhD project offered in the IPP winter call 2023/2024

Scientific Background

DNA damage is a constant threat to genome stability, and faithful DNA damage signaling and DNA repair play a fundamental role in counteracting ageing and cancer. DNA double-strand breaks (DSBs) are dangerous DNA lesions which are repaired by high-fidelity homologous recombination (HR) repair or the error-prone non-homologous end-joining (NHEJ) pathway. HR repair is frequently compromised in cancer cells. DSBs originate from exogenous and endogenous sources, and in particular highly proliferative cancer cells trigger the replication stress response, which activates the DNA damage signaling cascade. Our unpublished work identified a novel BRCA1-associated DNA damage signaling module with an essential role in the repair of extrinsic DSBs by regulating HR repair. Interestingly, our results indicate activity of this novel BRCA1-associated signaling module during replication stress, suggesting a role in the replication stress response evoked by stalled and/or broken DNA replication forks. This PhD project is aimed at unraveling the function of a novel BRCA1-associated signaling module in replication stress.

PhD Project: DNA damage signaling, DNA repair & cell fate control

This PhD project is embedded in the SFB 1361 consortium and aimed at elucidating the mechanisms interconnecting DNA damage signaling, DNA repair and cell fate choice. In particular, the signaling modules and machinery intertwining DNA double-strand break (DSB) repair upon replication stress will be analyzed from perspective of a novel BRCA1-associated signaling module discovered in our lab. To determine the function of the BRCA1-associated module at arrested and broken replication forks, a broad spectrum of techniques from cell biology, molecular biology, biochemistry and molecular genetics will be used. This highly interactive project will be performed in close collaboration with numerous Z-projects and members of the SFB 1361. The work program includes mass spectrometry-based replication fork-interactome analysis (iPOND), genome-wide mapping of the novel BRCA1-associated module using Cut&Tag seq, genome-wide analysis of DNA breaks using GLOE-seq and sBLISS, DNA fiber assays, confocal microscopy, flow cytometry, Crisp/Cas9-mediated gene editing, dTAG-mediated targeted degradation and protein-protein interaction analysis. The following questions will be addressed: 1. Is the BRCA1-associated module associated with stalled or broken replication forks, and how does act during replication stress? 2. What are the cellular (cell death, senescence) and molecular (DNA damage signaling, DNA repair & DNA replication fork) consequences of perturbing this module? 3. Does pharmacological or genetic perturbation of the module sensitize cancer cells to anti-cancer treatments?

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

Publications relevant to this project

Sigismundo G, Arseni L, Palacio-Escat N, Hofmann TG, Seiffert M, Krijgsveld J (2023). Multi-layered chromatin proteomics identifies vulnerabilities in DNA repair. Nucleic Acids Res 51:687-711.

Abu-Odeh M, Salah Z, Herbel C, Hofmann TG, Aqeilan RI (2014). WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response. Proc Natl Acad Sci USA 111: E4716-25.

Bitomsky N, Conrad E, Moritz C, Polonio-Vallon T, Sombroek S, Schultheiss C, Glas C, Greiner V, Herbel C, Mantovani F, del Sal G, Peri F, Hofmann TG (2013). Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc Natl Acad Sci USA 110: 115-25.