Genomic mapping reveals cisplatin disruption of protein phosphorylation signalling genome-wide.

Abstract

Cisplatin is a DNA-targeting chemotherapeutic. Here we investigate how the cisplatin-damaged gene (CDG) loci are linked to specific protein-driven signalling pathways. A human high mobility group protein 1 box a-based affinity probe has been constructed and 1,2-cisplatin-crosslinked DNA has been isolated before high throughput gene sequencing. Cisplatin damage to specific genes has been mapped in human lung cancer cells, and a total of 16 216 CDGs mapped with fold-enrichment >1.5. Surprisingly, bioinformatics analysis demonstrates that cisplatin targets most of the human protein kinase (PK) and phosphatase genes and is involved in 300 important cell signalling pathways (-log p > 4). The most associated key signalling pathways are sperm motility and protein kinase A. Notably, cisplatin damaged 85% (440) of human PK genes and 81% (110) of human protein phosphatase genes. This implies that cisplatin may disrupt protein phosphorylation signalling genome-wide, evidenced by a significant decrease in expression of a series of key PK genes.