Transcription of protein-coding genes is carried out by RNA polymerase II enzymes (RNAPII), which travel along the DNA to synthesize complementary RNA transcripts. When RNAPII encounters DNA damage in the template strand, this blocks its forward translocation and causes a genome-wide transcriptional arrest. To survive, cells must overcome this arrest by local DNA repair and effective restart of global gene transcription. Once stalled, RNAPII molecules themselves become major obstacles for DNA replication in dividing cells. Collisions between the transcription and replication machineries are emerging as a key source of genome instability. Our understanding of the different molecular mechanisms that repair transcription-blocking DNA lesions, or protect human cells against transcription–replications conflicts, is still far from complete. Transcription-coupled repair (TCR) is a specialized DNA repair pathway that selectively removes DNA lesions encountered while genes are actively transcribed. Through genome-wide CRISPR screens, we recently identified a network of novel TCR genes, centred around the previously uncharacterized ELOF1 gene. Drug-genetic network mapping revealed a defined set of genes that co-operates with ELOF1 in a common molecular pathway with a converging function at the intersection of TCR and DNA replication. In this project, we will combine our complementary expertise in TCR and transcription genomics (LUMC) with that in DNA replication stress pathways and genome-wide CRISPR screening (Amsterdam UMC) to dissect how the ELOF1 network orchestrates DNA repair during transcription and resolves transcription–replication conflicts in human cells. Our three objectives are: (1) to elucidate the mechanism by which ELOF1 directs TCR, (2) to dissect the roles of the ELOF1 network members in TCR, and (3) to define the role of the ELOF1 network in resolving conflicts between transcription and replication machineries. Dissecting these molecular mechanisms will reveal how the ELOF1 network safeguards genomic stability at the crossroads of transcription, repair and replication in human cells, which will provide an advanced, mechanistic understanding of the transcription-coupled DNA damage response.