Navigating Transcription-Replication Conflicts: Mechanisms of Resolution

Abstract

Transcription and DNA replication are essential for maintaining cellular function and genome integrity. However, their simultaneous activity on the same DNA template can result in transcription-replication conflicts (TRCs), a major source of genomic instability. These conflicts drive mutations and chromosomal rearrangements associated with cancer and neurodegenerative diseases. To prevent and resolve TRCs, cells employ strategies such as spatiotemporal coordination of transcription and replication and mechanisms to remove transcriptional obstacles. This review explores these processes across prokaryotic and eukaryotic cells, emphasizing conserved and specialized pathways that safeguard replication fork progression, transcription dynamics and genome stability. A key focus of this review is the resolution of stalled RNA polymerase II (RNAPII), a critical barrier to replication fork progression. Furthermore, we address key unresolved questions and discuss the therapeutic potential of targeting TRC resolution pathways. These insights underscore the importance of understanding how cells navigate the challenges posed by transcription and replication on the same DNA template.