Dose-dependent and compound-specific phospho-signalling responses after (geno)toxic treatment

Abstract

Genotoxic stressors may induce various types of DNA damage triggering the activation of the DNA damage response. However, the dose-dependency and the drug compound-specificity of the activated responses are unclear. Here, I first investigated the phospho-signalling responses induced by four chemical stressors with distinct modes of action and uncovered that, at equitoxic doses, even two ‘similar’ DNA damaging agents induced discrete and complex phosphorylation signalling cascades. Next, I investigated the ionising radiation (IR) dose-dependent responses using multi-omics and systems analyses to investigate the molecular and cellular responses to low and high doses of IR. I uncovered that the IR induced molecular responses have different dose-effect relationships. A minor part of the phosphorylation signalling and transcription involved in the DSB-related responses displayed a linear dose-effect relationship. Contrastingly, the reactive oxygen species (ROS) production-related molecular and cellular responses and DNA replication stress revealed complex dose-response relationships. LD uniquely activates ROS-related responses at multiple molecular levels, including proteome, phosphoproteome, nascent transcriptome and metabolome. Further work will be required to determine how these differences in molecular and cellular responses observed over hours after low and high doses impact the risk for cancer development that occurs over months and years.