Abstract

DNA-protein cross-links (DPCs) are super-bulky, helix-distorting DNA lesions that result from exposure to a variety of chemical and physical agents such as antitumor drugs, environmental/ occupational toxins, ionizing radiation, and endogenous free radical-generating systems. Due to their unusually bulky nature, DPCs are hypothesized to interfere with normal DNA-protein interactions required for DNA replication, transcription, and repair, potentially leading to mutagenesis, genotoxicity, and cytotoxicity. However, the biological outcomes of DPC lesions in cells are poorly understood because of their inherent structural complexity and the difficulty of generating DNA substrates containing structurally defined DPC for biological evaluation. Our long-term goal is to elucidate the role tha spontaneous and induced DPCs play in human disease and in the anticancer activity of common chemotherapeutic agents. The objectives of this application are to determine the biological consequences of DPC formation in human cells and to discover the mechanism(s) responsible for the removal of DPCs from DNA. Our studies will for the first time systematically examine the influence of DPCs on DNA repair and replication. Our central hypothesis is that, if not repaired, DPCs exert mutagenic and cytotoxic effects, significantly contributing to the biological effects of many known carcinogens and antitumor drugs. Collectively, these studies will provide significant new insights into the molecular and cellular biology of DPCs and are expected to fundamentally advance the fields of DNA repair, cancer biology, and molecular mechanisms of aging.

Public Health Relevance

Exposure to certain anticancer drugs, environmental pollutants, and chemicals naturally produced in the body can cause proteins to become trapped on DNA. The resulting DNA-protein cross-links, if not repaired, can have toxic effects or lead to cancer, aging, and heart disease. The goals of this project are to understand how human cells cope with DNA-protein cross-links.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES023350-03S1
Application #
9277636
Study Section
Program Officer
Shaughnessy, Daniel
Project Start
2014-05-21
Project End
2017-02-28
Budget Start
2017-01-18
Budget End
2017-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$50,000
Indirect Cost
$17,123

  Institution

Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Yang, Kun; Park, Daeyoon; Tretyakova, Natalia Y et al. (2018) Histone tails decrease N7-methyl-2'-deoxyguanosine depurination and yield DNA-protein cross-links in nucleosome core particles and cells. Proc Natl Acad Sci U S A 115:E11212-E11220
Pujari, Suresh S; Zhang, Yi; Ji, Shaofei et al. (2018) Site-specific cross-linking of proteins to DNA via a new bioorthogonal approach employing oxime ligation. Chem Commun (Camb) 54:6296-6299
Chesner, Lisa N; Campbell, Colin (2018) A quantitative PCR-based assay reveals that nucleotide excision repair plays a predominant role in the removal of DNA-protein crosslinks from plasmids transfected into mammalian cells. DNA Repair (Amst) 62:18-27
Groehler 4th, Arnold; Kren, Stefan; Li, Qinglu et al. (2018) Oxidative cross-linking of proteins to DNA following ischemia-reperfusion injury. Free Radic Biol Med 120:89-101
Basu, Ashis K (2018) DNA Damage, Mutagenesis and Cancer. Int J Mol Sci 19:
Chesner, Lisa N; Degner, Amanda; Sangaraju, Dewakar et al. (2017) Cellular Repair of DNA-DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane. Int J Mol Sci 18:
Ji, Shaofei; Shao, Hongzhao; Han, Qiyuan et al. (2017) Reversible DNA-Protein Cross-Linking at Epigenetic DNA Marks. Angew Chem Int Ed Engl 56:14130-14134
Pujari, Suresh S; Tretyakova, Natalia (2017) Chemical Biology of N5-Substituted Formamidopyrimidine DNA Adducts. Chem Res Toxicol 30:434-452
Pande, Paritosh; Ji, Shaofei; Mukherjee, Shivam et al. (2017) Mutagenicity of a Model DNA-Peptide Cross-Link in Human Cells: Roles of Translesion Synthesis DNA Polymerases. Chem Res Toxicol 30:669-677
Ming, Xun; Groehler 4th, Arnold; Michaelson-Richie, Erin D et al. (2017) Mass Spectrometry Based Proteomics Study of Cisplatin-Induced DNA-Protein Cross-Linking in Human Fibrosarcoma (HT1080) Cells. Chem Res Toxicol 30:980-995

Showing the most recent 10 out of 22 publications