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Adenomatous Polyposis Coli (APC) is a multifunctional tumor suppressor protein whose most well-known role is as a cytoplasmic regulator of the Wnt signaling pathway. APC, however, is capable of nucleocytoplasmic shuttling, giving APC a potential role in regulating several nuclear processes. One such process that APC is involved in is the DNA damage response (DDR) which ensures genomic integrity. Dysregulation of DDR can lead to increased mutation rates, which can cause the development of various diseases such as cancer. As APC mutations occur early in the development of 80% of human colorectal cancers, there is a possibility that the APC mutation can contribute to the dysregulation of DDR. Therefore, understanding APC’s role in DDR can serve as a foundation for the development of future CRC treatments. The overall objective of my dissertation is to determine APC’s role in the cellular response to a damaging agent, mainly UV.
In chapters 2 and 4, I focus on a potential APC role in responding to UV-induced DNA damage. I determined that expression of APC contributes to UV-induced DNA damage response, potentially through increasing the efficiency of stalled replication fork repair. Additionally, X-ray exposure yielded different responses in APC+ and APC- cells, but with APC- cells seemingly more able to repair the damage, which was the opposite of those observed with UV. These results highlight the possibility that APC plays varying roles in response to different inducers of DNA damage.
To aid in elucidating the mechanism behind the observed differences in the UV-exposed APC+ and APC- cells, I performed RNA sequencing. The gene expression profiles revealed differences between APC+ and APC- samples that support known APC functions. A significant interaction was identified between UV-response and APC status. Differentially expressed genes at this intersection unveiled a novel APC function to repress transcription in response to UV.
Although previous studies have demonstrated a role for APC in specific DDR pathways, this dissertation represents the first mechanistic study of APC function in the cellular response to UV. In this work, I present a role for APC in the efficient repair of UV-induced stalled replication forks. The RNA-sequencing results also reaffirmed and added a new dimension to previously known roles of APC, as well as presented a potential novel function of APC in UV response.