Transcription-associated DNA breaks and cancer: A matter of DNA topology.

Transcription is an essential cellular process but also a major threat to genome integrity. Transcription-associated DNA breaks are particularly detrimental as their defective repair can induce gene mutations and oncogenic chromosomal translocations, which are hallmarks of cancer. The past few years have revealed that transcriptional breaks mainly originate from DNA topological problems generated by the transcribing RNA polymerases. Defective removal of transcription-induced DNA torsional stress impacts on transcription itself and promotes secondary DNA structures, such as R-loops, which can induce DNA breaks and genome instability. Paradoxically, as they relax DNA during transcription, topoisomerase enzymes introduce DNA breaks that can also endanger genome integrity. Stabilization of topoisomerases on chromatin by various anticancer drugs or by DNA alterations, can interfere with transcription machinery and cause permanent DNA breaks and R-loops. Here, we review the role of transcription in mediating DNA breaks, and discuss how deregulation of topoisomerase activity can impact on transcription and DNA break formation, and its connection with cancer.