PhD defence M.E. (Marit) Geijer
- Prof.dr. W. Vermeulen
- Dr. J.A.F. Marteijn
On Wednesday31 March 2021, M.E. Geijer will defend her PhD dissertation, entitled: ‘Dissecting the DNA Damage-Induced Transcription Stress Response’.
The genetic code for all organisms is stored in the nucleotide sequence of their DNA. Protecting the genetic code is essential to faithfully transcribe the genetic information of our DNA into RNA. Progression of RNA polymerase II (Pol II), the protein involved in RNA transcription, is regularly impeded by DNA damage. Such transcription-blocking lesions (TBLs) can be induced by endogenously produced reactive oxygen species formed as side products from metabolic processes, or by exogenous sources such as UV irradiation and chemicals. Elongating Pol II that encounters a TBL can cause reduced transcription fidelity that eventually can result in mutant RNA transcripts or can even completely block the synthesis of new mRNAs. This transcriptional burdens can lead to reduced cell function and eventually induce DNA damage-induced aging. Moreover, if stalling of Pol II is persistent, this can induce the formation of R-loops and induce transcriptionreplication conflicts that can lead to genome instability and eventually can induce cancer. Collectively, these transcriptional impediments and consequences are referred to as the DNA damage-induced transcription stress response. To prevent these detrimental effects of prolonged stalling, cells have a dedicated repair mechanism called transcription-coupled nucleotide excision repair (TC-NER) that repairs TBLs and is initiated upon stalling of Pol II at a lesion. Lesion-stalled Pol II results in the recruitment of TC-NER factors that help to recognize and verify the lesion and excise the damaged part of the DNA. Eventually, new DNA is synthesized and the DNA is ligated after which transcription can be resumed. During the repair reaction, Pol II needs to be displaced to allow repair factors to access the lesion. Moreover, in addition to the direct consequences of stochastic Pol II stalling, transcription is also highly regulated at a genome-wide level, as part of the DNA damage-induced transcription stress response. These include complex activation and subsequent inhibition of transcription initiation, a release of promoter-paused Pol II into the gene body and changes in alternative splicing. These events are all important for cells to cope with TBLs and contribute to recognizing the lesions, initiating repair and maintaining transcription fidelity.
Due to corona, the PhD defences do not take place publicly in the usual way in the Senate Hall or in the Professor Andries Querido Room. The candidates will defend their dissertation either in a small group or online.