Bleomycin analogues preferentially cleave at the transcription start sites of actively transcribed genes in human cells

Bleomycin (BLM) is a cancer chemotherapeutic agent that is used in the treatment of several types of tumours. The cytotoxicity of three BLM analogues, BLM Z, 6′-deoxy-BLM Z and zorbamycin (ZBM), was determined in human HeLa cells in comparison with BLM. It was found that the IC50 values were 2.9 μM for 6′-deoxy-BLM Z, 3.2 μM for BLM Z, 4.4 μM for BLM and 7.9 μM for ZBM in HeLa cells. Using next-generation Illumina DNA sequencing techniques, the genome-wide cleavage of DNA by the BLM analogues was determined in human HeLa cells and compared with BLM. It was ascertained that BLM, 6′-deoxy-BLM Z and ZBM preferentially cleaved at the transcription start sites of actively transcribed genes in human cells. The degree of preferential cleavage at the transcription start sites was quantified and an inverse correlation with the IC50 values was observed. This indicated that the degree of preferential cleavage at transcription start sites is an important component in determining the cytotoxicity of BLM analogues.

Graphical abstractDownload high-res image (110KB)Download full-size image