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

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

Author information

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

PMID:
30633903
PMCID:
PMC6344048
[Available on 2020-01-10]
DOI:
10.1016/j.cell.2018.12.008

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