Transcription-Replication Conflicts: Unlocking New Frontiers in Cancer

Genome instability (GIN) is a cell pathology linked to cancer promotion and tumor evolution. Transcription is an essential cellular process but also a potential source of DNA damage and GIN. Transcription-replication conflicts (TRCs) are a predominant source of GIN, and defective TRC resolution may seriously compromise genome integrity. Importantly, chromatin dynamics helps orchestrate the response to TRCs to preserve genome integrity. Multiple epigenetic deficiencies have been shown to cause transcription-induced replication stress, resulting in DNA breaks and mutations. Consistently, chromatin alterations are frequent in cancer and correlate with increased mutation burden at TRC sites in tumors. Here, we review our current knowledge of TRC processing, the consequences of its dysfunction, and its relevance in cancer. We focus on the interplay between the DNA damage response (DDR) and chromatin dynamics and discuss the clinical potential of targeting TRCs as anticancer strategies and drugging the associated epigenetic signatures.