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

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

doi:10.1016/j.cell.2018.12.008

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

Cell. 2019 Jan 10;176(1-2):127-143.e24. doi: 10.1016/j.cell.2018.12.008.

Authors

Jun Xia¹, Li-Ya Chiu², Ralf B Nehring³, María Angélica Bravo Núñez³, Qian Mei⁴, Mercedes Perez², Yin Zhai⁵, Devon M Fitzgerald³, John P Pribis¹, Yumeng Wang⁶, Chenyue W Hu⁷, Reid T Powell⁸, Sandra A LaBonte⁹, Ali Jalali¹⁰, Meztli L Matadamas Guzmán³, Alfred M Lentzsch², Adam T Szafran¹¹, Mohan C Joshi¹², Megan Richters³, Janet L Gibson³, Ryan L Frisch³, P J Hastings¹³, David Bates¹², Christine Queitsch¹⁴, Susan G Hilsenbeck¹⁵, Cristian Coarfa¹⁶, James C Hu⁹, Deborah A Siegele¹⁷, Kenneth L Scott¹⁸, Han Liang¹⁹, Michael A Mancini¹⁶, Christophe Herman²⁰, Kyle M Miller²¹, Susan M Rosenberg²²

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Molecular Biosciences, LIVESTRONG Cancer Institute of the Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Systems, Synthetic and Physical Biology Program, Rice University, Houston, TX 77030, USA.
⁵ Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Bioengineering, Rice University, Houston, TX 77030, USA.
⁸ Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA.
⁹ Department of Biochemistry and Biophysics, Texas A&M University and Texas AgriLife Research, College Station, TX 77843, USA.
¹⁰ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
¹⁵ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁶ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Biology, Texas A&M University, College Station, TX 77843, USA.
¹⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
²⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: herman@bcm.edu.
²¹ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Biosciences, LIVESTRONG Cancer Institute of the Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: kyle.miller@austin.utexas.edu.
²² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA; Systems, Synthetic and Physical Biology Program, Rice University, Houston, TX 77030, USA. Electronic address: smr@bcm.edu.

Abstract

DNA damage provokes mutations and cancer and results from external carcinogens or endogenous cellular processes. However, 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 a poor prognosis. Half of the tested human homologs promote DNA damage and mutation when overproduced in human cells, with DNA damage-elevating mechanisms like those in E. coli. 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.

Keywords: DNA damage response; DNA double-strand breaks; DNMT1; Escherichia coli; cancer; evolution; genome instability; human cells; microbial cancer models; replication fork reversal.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Bacterial Proteins / metabolism
Chromosomal Instability / physiology
DNA Damage / genetics*
DNA Damage / physiology*
DNA Repair / physiology*
DNA Replication / physiology
DNA-Binding Proteins / metabolism
Escherichia coli / metabolism
Genomic Instability
Humans
Membrane Transport Proteins / physiology
Mutagenesis
Mutation
Transcription Factors / metabolism

Substances

Bacterial Proteins
DNA-Binding Proteins
Membrane Transport Proteins
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding