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.

转录是一个重要的细胞过程，但也是对基因组完整性的主要威胁。转录相关的 DNA 断裂尤其有害，因为它们的缺陷修复会导致基因突变和致癌染色体易位，这是癌症的标志。过去几年表明，转录中断主要源于转录 RNA 聚合酶产生的 DNA 拓扑问题。转录诱导的 DNA 扭转应力的缺陷去除会影响转录本身并促进二级 DNA 结构，例如 R 环，这会导致 DNA 断裂和基因组不稳定。矛盾的是，当它们在转录过程中放松 DNA 时，拓扑异构酶会引入 DNA 断裂，这也会危及基因组的完整性。通过各种抗癌药物或通过 DNA 改变来稳定染色质上的拓扑异构酶会干扰转录机制并导致永久性 DNA 断裂和 R 环。在这里，我们回顾了转录在介导 DNA 断裂中的作用，并讨论了拓扑异构酶活性的失调如何影响转录和 DNA 断裂的形成，以及它与癌症的关系。