Advisor
Howlett, Niall [faculty advisor, Department of Cell and Molecular Biology]
Date
5-2009
Keywords
cancer; leukemia; DNA repair
Abstract
Our bodies are constantly exposed to a variety of substances that damage our DNA, such as ultraviolet radiation, environmental chemicals, and the reactive by-products of our metabolism. To prevent the harmful effects that may result from such damage, our cells possess multiple DNA repair mechanisms. However, if their ability to repair damaged DNA is somehow impaired, cells are more likely to accumulate potentially harmful mutations, including those that may lead to the development of cancer.
In Fanconi anemia (FA), a rare recessive genetic disorder, a defect in a DNA repair pathway results in increased sensitivity to a particular type of damage. FA is characterized by congenital abnormalities, progressive bone marrow failure, and increased susceptibility to cancer. Interesting connections have been made between FA and cancer, including findings that several of the FA genes are also breast cancer susceptibility genes. Despite recent progress in this area, much about how exactly the pathway functions on a molecular level to repair damaged DNA is still unclear. Thus, further research on this rare disease will be valuable for both the treatment of FA patients and our understanding of cancer in general.
For my honors project, I investigated whether there is any link between the FA pathway and p21, a critical DNA damage response protein that halts replication and progression through the cell cycle until the damage is repaired. To determine whether p21 plays a role in the FA pathway, I examined whether FANCD2 monoubiquitination (a key event in activation of the pathway) and expression of p21 in cells are coordinated following exposure to UV irradiation and other types of DNA damage, whether FANCD2 monoubiquitination is impaired in cells lacking p21, and whether inhibition of p21 degradation affects FANCD2 monoubiquitination.