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 loci are linked to specific protein-driven signalling pathways. Using forward chemical genetics methods, cisplatin damage to specific genes has been mapped in human lung cancer cells, a total of 16216 cisplatin-damaged genes (CDGs) with fold-enrichment > 1.5. Surprisingly, bioinformatics analysis demonstrates that cisplatin targets the majority of human protein kinase and phosphatase genes and involved in 300 core signalling pathways (-log p >4). The most associated key signalling pathways are sperm motility and protein kinase A. The highest related disease is cancer, and tissue toxicities related to CDGs are about hepato- and nephro- toxicities. Notably, cisplatin damaged 85% (440) of human protein kinase genes and 81% (110) of human protein phosphatase genes. This suggests that cisplatin acts as a multi-targeting protein-phosphorylation regulator, confirmed by a significant decrease in expression of a series of key protein kinase genes. These results reveal that cisplatin disrupts protein phosphorylation signalling genome-wide. Key points summarising the key messages of your articleA total of 16216 genes damaged by the clinical drug cisplatin in human lung cancer cells were identified using a forward chemical genetics method. Bioinformatics analysis revealed that cisplatin targets 85% of protein kinase and 81% of phosphatase genes. Cisplatin acts as a multi-targeting protein-phosphorylation regulator, disrupting protein phosphorylation signalling genome-wide. The disturbance of protein phosphorylation by cisplatin can be related to anticancer activity and tissue toxicities of the drug. These findings suggests novel strategies for rational design of next-generation anticancer metallodrugs involving specific targeting of protein phosphorylation.