Author:
Xia Jun,Chiu Li-Ya,Nehring Ralf B.,Bravo Núñez María Angélica,Mei Qian,Perez Mercedes,Zhai Yin,Fitzgerald Devon M.,Pribis John P.,Wang Yumeng,Hu Chenyue W.,Powell Reid T.,LaBonte Sandra A.,Jalali Ali,Matadamas Guzmán Meztli L.,Lentzsch Alfred M.,Szafran Adam T.,Joshi Mohan C.,Richters Megan,Gibson Janet L.,Frisch Ryan L.,Hastings P.J.,Bates David,Queitsch Christine,Hilsenbeck Susan G.,Coarfa Cristian,Hu James C.,Siegele Deborah A.,Scott Kenneth L.,Liang Han,Mancini Michael A.,Herman Christophe,Miller Kyle M.,Rosenberg Susan M.
Abstract
SUMMARYDNA 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 inEscherichia coliand 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 inE. 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.
Publisher
Cold Spring Harbor Laboratory