Interference between DNA replication and transcription as a cause of genomic instability

Replication and transcription are key aspects of DNA metabolism that take place on the same template and potentially interfere with each other. Conflicts between these two activities include head-on or co-directional collisions between DNA and RNA polymerases, which can lead to the formation of DNA breaks and chromosome rearrangements. To avoid these deleterious consequences and prevent genomic instability, cells have evolved multiple mechanisms preventing replication forks from colliding with the transcription machinery. Yet, recent reports indicate that interference between replication and transcription is not limited to physical interactions between polymerases and that other cotranscriptional processes can interfere with DNA replication. These include DNA-RNA hybrids that assemble behind elongating RNA polymerases, impede fork progression and promote homologous recombination. Here, we discuss recent evidence indicating that R-loops represent a major source of genomic instability in all organisms, from bacteria to human, and are potentially implicated in cancer development.