Topoisomerase Regulation of Cancer Gene Expression.

Abstract

Under hyperproliferative conditions, escalation of genomic activity provokes high levels of DNA mechanical stress. Cancer cells cope with this stress through topoisomerase activity. Topoisomerases support genome-wide programs, including those driven by oncogenes and tumor suppressors, by adjusting the supercoiling and by interacting with the regulatory complexes involved in transcription, replication, and chromatin transactions. Topoisomerases also manage DNA conformational alterations that control gene activity. However, when the topological stress from oncogene-driven processes exceeds topoisomerase capacity, aberrant structures associated with DNA damage arise. These abnormalities include R-loop formation during transcription and replication. Excessive supercoiling also creates transcription-replication conflicts triggering DNA damage. Topoisomerase catalytic failure elicits topological dysregulation and DNA damage. This damage contributes further to tumorigenesis and tumor progression. The roles of topoisomerases in various genetic processes have been widely described, but the cancer-specific functions of topoisomerases are incompletely understood. Here, we summarize the crucial roles played by topoisomerases in cancer.