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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES023350-01A1
Application #
8759022
Study Section
Special Emphasis Panel (ZRG1-OBT-S (02))
Program Officer
Shaughnessy, Daniel
Project Start
2014-05-21
Project End
2019-02-28
Budget Start
2014-05-21
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$387,128
Indirect Cost
$107,607
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Weerasooriya, Savithri; Jasti, Vijay P; Basu, Ashis K (2014) Replicative bypass of abasic site in Escherichia coli and human cells: similarities and differences. PLoS One 9:e107915