Transcription–replication conflicts: how they occur and how they are resolved

Transcription and replication occur at high frequency in cells. As they share the same DNA template, a high incidence of encounters is expected between the transcription and replication machineries, which can cause transcription–replication conflicts, DNA damage and genomic instability.Cells have developed different strategies to reduce or prevent transcription–replication encounters, from genome organization favouring co-orientation of replication and transcription to specific mechanisms to avoid or resolve such collisions.Transcription–replication collisions can occur owing to cis structural features, such as changes in DNA supercoiling, or secondary DNA structures, including hairpins, G-quadruplexes and RNA–DNA hybrids, which have the capacity to hinder replication fork progression.The factors that minimize collisions include the transcription machinery itself and mRNA-processing proteins, as well as factors that help or facilitate replication progression, such as DNA helicases and topoisomerases or chromatin-remodelling complexes.The DNA damage response is able to sense a stalled replication fork caused by transcription–replication conflicts and to promote various mechanisms that solve the collisions. This includes, for example, the removal of the RNA polymerase and the action of various repair pathways, such as the Fanconi anaemia pathway.A better understanding of the dynamics of replication and transcription machineries will help to clarify the importance of transcription–replication collisions as a source of genomic instability and to open up the possibility of using them as selective targets in cancer therapy.