Correct gene transcription by RNA polymerase II is essential for proper cell function. However, DNA damage, such as that caused by UV light or chemicals, can block transcription by RNA polymerases, leading to cellular dysfunction and cell death, ultimately resulting in DNA damage-induced aging and genome instability. Cells counteract these harmful effects through transcription-coupled repair (TCR), which specifically removes DNA damage in genes, thus protecting transcription. Our lab has identified several key factors that provide new insights into 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).

The Role

In this project, we will investigate how mechanical stress impacts transcription-coupled repair and transcription stress in differentiated human neurons. Neurons, being long-lived and non-dividing cells, rely heavily on continuous and accurate transcription, yet they are also subjected to changes in cellular and nuclear mechanics that may disrupt genome stability. By utilizing iPSC-derived neurons, CRISPR-Cas9 gene editing, and advanced live-cell imaging techniques, we will examine how mechanical stress affects transcription stress and transcription-coupled repair, as well as how defects in these pathways influence the mechanical properties and stress responses of neurons. This research will offer new mechanistic insights into the relationship between mechanical stress, transcription integrity, and DNA repair, potentially elucidating why differentiated neurons are particularly susceptible during aging and neurodegenerative diseases.