PhD-student to study transcription stress in neurons

Correct gene transcription by RNA polymerase II to transcribe new RNA molecules is crucial for proper cell function. However, transcription by RNA polymerases can be blocked by DNA damage, for example by UV-light or other chemicals. This transcription-blocking DNA damage can therefore cause cellular dysfunction and cell death, eventually resulting in DNA damage-induced aging and genome instability. Cells counteract these deleterious effects by transcription-coupled repair (TCR), which specifically removes DNA damage in our genes, thereby safeguarding transcription. Our lab has identified several important factors that provided novel insights in this repair pathway (van Sluis et al., Nature Cell Biology 2024; Ramadhin et al., Molecular Cell 2024; van Toorn et al., Molecular Cell, 2022; Geijer et al., Nature Cell Biology, 2021; Tresini et al. Nature, 2015; Schwertman et al. Nature Genetics, 2012).

In this project, we will investigate how mechanical stress affects transcription-coupled repair and transcription stress in differentiated human neurons. Neurons are long-lived, non-dividing cells that depend strongly on continuous and accurate transcription, but they are also exposed to changes in cellular and nuclear mechanics that may interfere with genome stability. Using iPSC-derived neurons, CRISPR-Cas9 gene editing and advanced live-cell imaging, we will investigate how mechanical stress influences transcription stress and transcription-coupled repair, and how defects in these pathways alter the mechanical properties and stress responses of neurons. This project will provide new mechanistic insight into the interplay between mechanical stress, transcription integrity and DNA repair, and may help explain why differentiated neurons are particularly vulnerable during aging and neurodegenerative disease.