Postdoc on "Tissue specific responses to DNA damage-induced transcription stress"

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. These transcription-blocking DNA lesions can 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 TBLs 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), uncovered that DNA damage-induced transcription-stress is an important cause of age-related diseases (Schumacher, Nature, 2021) and identify mechanisms that could counteract DNA-damage induced aging (Vermeij, Nature, 2016).

Specific cell types, including neurons, appeared more severely affected by TBLs compared to other tissues. However, surprisingly little is known about the tissue-specific responses (e.g. brain, muscle, liver) to DNA damage that blocks transcription. In this project we will study the effects of DNA damage on transcription and repair in different cell and tissue types using state-of-the-art live-cell imaging approaches in iPSC-based differentiation models and in mouse models. To do so, we have developed GFP-Pol II knock-in cells and a mouse model that expresses GFP-tagged Pol II at endogenous levels (Steurer, PNAS, 2018), which can be used as a sensitive imaging tool to study the cell-specific effects of DNA damage on transcription. Together this will result in detailed insight in the types of DNA damage that contribute to transcription-stress, the involved repair pathways, and additional transcriptional responses to DNA damage in different tissues which will lead to a better understanding of the underlying mechanisms of the aging process.