We recently constructed a POL B mutant mouse model and surprisingly these mice develop Systemic Lupus Erythematosus (SLE). POL B encodes the DNA polymerase beta protein, which functions in base excision repair (BER). BER removes DNA damage induced by ionizing radiation (IR), and reactive oxygen and nitrogen species (RONs) and an imbalance in the repair of base damage induced by IR and RONs leads to the accumulation of BER intermediates. Interestingly, individuals with SLE are unable to efficiently repair base damage induced by IR and are frequently excluded from treatment that includes IR. Our preliminary data suggest that oxidative DNA damage in our POL B defective mice results in the accumulation of BER intermediates that lead to the development of SLE. The broad long-term objective of the proposed research is to understand how aberrant DNA repair leads to SLE and to understand the interactions between genetic and environmental factors that result in SLE. In this proposal we will focus on DNA repair genes that function in BER to repair damage and that can be induced by IR and RONs. In the first aim, we will test the hypothesis that aberrant canonical base excision repair is linked to SLE in mice. In the second aim, we will test the hypothesis that aberrant co-opted DNA repair used in specialized cellular processes is linked to SLE in mice. We will use a combined biological, biochemical and genetic approach in this project. We will determine if oxidative stress-inducing agents induce SLE in our POL B mouse model and if antioxidants and genetic factors influence SLE development. These studies have significant potential to advance our fundamental understanding of how aberrant repair of DNA base damage leads to SLE and could impact treatment of this disease in the future.

Public Health Relevance

The goal of this project is to understand how aberrant DNA repair leads to the development of lupus. We have a unique mouse model of lupus and will characterize this mouse model to understand how lupus develops. Our project has strong potential to lead to new treatments for this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019179-08
Application #
9404999
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Reinlib, Leslie J
Project Start
2010-07-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Meas, Rithy; Burak, Matthew J; Sweasy, Joann B (2017) DNA repair and systemic lupus erythematosus. DNA Repair (Amst) 56:174-182
Nemec, Antonia A; Bush, Korie B; Towle-Weicksel, Jamie B et al. (2016) Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer-Associated R438W DNA Polymerase Lambda Protein. Mol Cancer Res 14:1068-1077
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