The central theme of my lab is how cells cope with the severe consequences of transcription-blocking DNA damage (Marteijn, Nat.Reviews.Mol.Cell.Biol,2015). We focus on how these DNA lesions are repaired by Transcription-Coupled Repair (TCR) and what theirs effects are on RNA polymerase and the related DNA damage response (DDR). TCR is a sub-pathway of Nucleotide Excision Repair (NER), which is an important DNA repair mechanism able to remove a broad range of different types of helix-distorting DNA lesions. NER protects organisms against DNA damage-induced carcinogenesis and premature aging. Its significance is illustrated by the severe clinical consequences associated with inherited defects in NER, including the cancer-prone disease Xeroderma Pigmentosum (XP) and the premature ageing of Cockayne Syndrome (CS) patients.
Using a combination of quantitative proteomics with state of the art live cell imaging approaches we study the consequences of transcription stress and the TCR mechanism in the living cell. Research questions include how TCR is initiated and how this this multi-step reaction is controlled by protein-protein interactions and posttranslational modifications. Furthermore, we study the link between transcription stalling and genome instability. As many currently used chemotherapeutics induce stalling of RNA polymerase Pol II, a better understanding of these processes will help to improve effectiveness of current therapies and to decrease their side effects, such as severe neurotoxicity.