Bacteria-to-Human Protein Networks Reveal Origins of Endogenous DNA Damage

Abstract

DNA damage provokes mutations and cancer, and results from external carcinogens or endogenous cellular processes. Yet, the intrinsic instigators of endogenous DNA damage are poorly understood. Here we identify proteins that promote endogenous DNA damage when overproduced: the DNA “damage-up” proteins (DDPs). We discover a large network of DDPs in Escherichia coli and deconvolute them into six function clusters, demonstrating DDP mechanisms in three: reactive-oxygen increase by transmembrane transporters, chromosome loss by replisome binding, and replication stalling by transcription factors. Their 284 human homologs are over-represented among known cancer drivers, and their RNAs in tumors predict heavy mutagenesis and poor prognosis. Half of tested human homologs promote DNA damage and mutation when overproduced in human cells, with DNA-damage-elevating mechanisms like those in E. coli . Together, our work identifies networks of DDPs that provoke endogenous DNA damage and may reveal DNA-damage-associated functions of many human known and newly implicated cancer-promoting proteins. A large network of proteins in bacteria promotes endogenous DNA damage when upregulated and these are shown to have human homologs that form a cancer-predictive network.