PT  - JOURNAL ARTICLE
AU  - Jun Xia
AU  - Li-Ya Chiu
AU  - Ralf B. Nehring
AU  - María Angélica Bravo Núñez
AU  - Qian Mei
AU  - Mercedes Perez
AU  - Yin Zhai
AU  - Devon M. Fitzgerald
AU  - John P. Pribis
AU  - Yumeng Wang
AU  - Chenyue W. Hu
AU  - Reid T. Powell
AU  - Sandra A. LaBonte
AU  - Ali Jalali
AU  - Meztli L. Matadamas Guzmán
AU  - Alfred M. Lentzsch
AU  - Adam T. Szafran
AU  - Mohan C. Joshi
AU  - Megan Richters
AU  - Janet L. Gibson
AU  - Ryan L. Frisch
AU  - P.J. Hastings
AU  - David Bates
AU  - Christine Queitsch
AU  - Susan G. Hilsenbeck
AU  - Cristian Coarfa
AU  - James C. Hu
AU  - Deborah A. Siegele
AU  - Kenneth L. Scott
AU  - Han Liang
AU  - Michael A. Mancini
AU  - Christophe Herman
AU  - Kyle M. Miller
AU  - Susan M. Rosenberg
TI  - Bacteria-to-human protein networks reveal origins of endogenous DNA damage
AID  - 10.1101/354589
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 354589
4099  - http://biorxiv.org/content/early/2018/06/26/354589.short
4100  - http://biorxiv.org/content/early/2018/06/26/354589.full
AB  - DNA damage provokes mutations and cancer, and results from external carcinogens or endogenous cellular processes. Yet, the intrinsic instigators of DNA damage are poorly understood. Here we identify proteins that promote endogenous DNA damage when overproduced: the DNA-damaging proteins (DDPs). We discover a large network of DDPs in Escherichia coli and deconvolute them into six DNA-damage-causing 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 expression in tumors predicts heavy mutagenesis and poor prognosis. Half of tested human homologs, when overproduced in human cells, promote DNA damage and mutation, with DNA-damaging mechanisms like those in E. coli. Together, our work reveals DDP networks that provoke endogenous DNA damage and may indicate functions of many human known and newly implicated cancer-promoting proteins.