Network perturbation analysis of gene transcriptional profiles reveals protein targets and mechanism of action of drugs and influenza A viral infection

Noh, Heeju; Shoemaker, Jason E; Gunawan, Rudiyanto

In comparison to DeMAND and DE analysis, ProTINA was further able to detect a specific MoA of mitomycin C, whose DNA crosslinking activity is expected to prompt a particular DNA repair process called the fanconi anemia pathway (57) . The fanconi anemia pathway relies on a specific protein complex to ubiquitinate Fanconi Anemia Group D2 Protein (FANCD2) and Fanconi Anemia Group I Protein (FANCI), as well as two homologous recombination (HR) repair proteins, namely Breast Cancer Type 1 Susceptibility Protein (BRCA1) and RAD51 Recombinase (RAD51) (58) . In ProTINA analysis, the average rank of FANCD2, FANCI, BRCA1, and RAD51 was within top 100 for mitomycin C, while the average rank of those proteins was much >100 for the other DNA damaging agents (see Supplementary Table S7 ). However, the specific activation of the fanconi anemia pathway by mitomycin C was not detected by DeMAND or DE analysis. Thus, ProTINA provided more sensitive and specific indications for the mechanism of action of compounds than De-MAND and DE.