Additionally, ISP I induces R-loop formation outside the nucleolus at sites of DNA damage; impairs rRNA transcription in a dose-dependent fashion, so that NPM1 protein level falls and p53 rises; and substantially enhances ROS activity through the JNK2/TIF-IA pathway, all of which induce nucleolar dysfunction and enhance sensitivity to ROS in tumor cells. This evidence concerns the gene RRN3 and neoplasm.