Maintaining genome integrity is crucial, especially in protein-encoding genes. DNA damage in genes can give rise to harmful mutations, but it can also directly obstruct the progress of transcribing RNA polymerase II (RNAPII), thereby blocking gene expression. Not surprisingly, repair pathways have evolved that specifically target lesions that stop RNAPII during its journey across a gene, so-called transcription-coupled repair pathways. As an alternative and ¿last resort¿, damage-stalled RNAPII can also be permanently removed by ubiquitylation/degradation, clearing the gene for repair by other means. Together, transcription-coupled repair and RNAPII ubiquitylation constitute an essential axis in the response to DNA damage.Conversely, while transcription is essential and therefore protected by a variety of mechanisms, it also itself comes at a cost for genome integrity. For example, high levels of transcription are correlated with breaks at fragile chromosome sites, mutagenesis and elevated levels of DNA recombination. Research into how the genome-destabilizing effects of transcription are minimized is still at an early stage, but insight into this research area is essential for our general appreciation of the regulatory mechanisms at play in the interface between transcription and other DNA-related processes, as well as for the understanding of processes underlying genome instability.This proposal describes how funding from the ERC will enable us to use a multi-disciplinary approach to shed new light on fundamental and disease-relevant processes, which are crucial for maintaining genome integrity during active transcription.