A double stand break is a type of DNA damage which involves the severing of one DNA molecule into two parts. Unrepaired breaks are harmful to living organisms since they lead to cell death. However, cells that do repair their breaks can also suffer detrimental outcomes if the repair is associated with DNA alteration. Repair pathways can be error free, restoring the DNA to its pristine condition, or error-prone, leading to mistakes in DNA repair. The latter may lead to chromosomal abnormalities frequently associated with changes in gene structure and regulation. The effects of these errors on chromosome structure and gene regulation often promote tumors and are frequently found in cells of cancer patient. A low level of DNA breaks occur due to normal cellular process and some are environmentally induced (for example, radiation therapy and/or chemotherapeutic drugs). If this damage is not properly repaired, it can contribute to cancer reoccurrence. Understanding processes involved in how a particular DNA repair mechanism is selected will be fundamental for determining how cancer progresses as well as for cancer treatment. The long-term goal of this research is to identify mechanisms involved in selecting an error-free repair vs. an error-prone repair pathway. This proposal focuses on identifying proteins and mechanisms involved in this choice. Studies are proposed to understand how processing of double stand break affects such a decision. We will use C. elegans, a multi- cellular animal model system which allows us to preform genetic assays for DNA repair in whole organism, at a low cost and with efficient time scale. Using a newly identified mutant in a key repair gene, we will examine DNA processing independently of DNA damage in the C. elegans germline. Furthermore, we will identify new mechanisms directly regulating a key protein involved in this processing. To complement this analysis, we will study the germline as a model for the cell-cycle control of DNA processing by designing a system for targeting DNA damage to particular regions of the germline. The conservation of genes and pathways between this animal model and humans will serve as efficient approach for discovery of genes in humans affecting the formation and progression of cancer. Understanding how accurate versus error-prone pathways are selected will be essential for developing anti-cancer therapies utilizing DNA damage to destroy cancer cells without harming healthy non-cancerous cells.

Public Health Relevance

The findings of these proposed studies will benefit public health by enhancing the understanding of DNA repair, which is essential for maintaining the integrity of the genome. Erroneous DNA repair processes contribute to cancer formation and progression. Novel insights into how a particular DNA repair mechanisms is chosen will be an essential step toward improving the diagnosis, prevention and treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM112657-05
Application #
9616277
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Willis, Kristine Amalee
Project Start
2015-01-15
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Iowa
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242