Nat Rev Mol Cell Biol Transcription-replication conflicts 1 Transcription--replication conflicts: how they occur and how they are resolved Tatiana García-Muse & Andrés Aguilera Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla, Seville, Spain corresponding author: aguilo@us.es Abstract The frequent occurrence in cells of transcription and DNA replication results in many encounters and thus conflicts between the transcription and replication machineries. These conflicts constitute a major intrinsic source of genome instability, which is a hallmark of cancer cells. How the replication machinery progresses through a DNA occupied by an RNA polymerase is an old question. Here we review recent data on the biological relevance of transcription-replication conflicts and the factors and mechanisms involved in either preventing or resolving them in eukaryotes. With this we aim to provide our current view of how transcription can generate obstacles to replication, including torsional stress and non-B DNA structures, and of the different cellular processes that have evolved to solve them. Introduction Genomes are templates for multiple biological processes, including transcription, epigenetic modifications, DNA replication, DNA repair and chromosome segregation. In a number of cases, crosstalk between different processes occurring at the DNA may have a positive effect, as in the case of transcription-coupled repair [G] 1 . However, in