Correct transcription by RNA polymerase II (Pol II) to generate RNA is crucial for proper cell function. However, transcription is continuously compromised by DNA damage. Transcription-blocking DNA damage causes 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 thereby safeguarding transcription (Lans, Nature reviews Molecular Cell Biology, 2019). Our labs have identified several important factors in this repair pathway (Schwertman, Nature Genetics, 2012; Dinant, Molecular Cell, 2013; Tresini, Nature, 2015; Geijer Nature Cell Biology, 2021; van Toorn, Mol. Cell, 2022), uncovered that DNA damage-induced transcription-stress is an important cause of age-related diseases (Schumacher, Nature, 2021) and identified mechanisms that could counteract DNA-damage induced aging (Vermeij, Nature, 2016).
In this project, the Postdoc will study the cellular responses to transcription-blocking DNA damage using state-of-the-art live cell imaging approaches. The applicant will use and further develop fluorescent knock-in cell lines expressing Pol II (Steurer, PNAS, 2018) and TC-NER factors (Geijer Nature Cell Biology, 2021) to study the effects of DNA damage on transcription and uncover the molecular mechanism of TCR. These studies will include the use of cellular differentiation models to uncover tissue-specific responses (e.g. brain, muscle, liver) to DNA damage that blocks transcription, and single-molecule analysis to provide in-depth insight in the molecular mechanism how transcription-blocking DNA damage is repaired. Together this will result in detailed insights in how DNA damage interferes with transcription and will lead to a better understanding of the underlying mechanisms of the aging process.
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