Askin, Kristin Fabre, authorUllrich, Robert L., advisorWeil, Michael M., advisor2024-03-132024-03-132008https://hdl.handle.net/10217/237561The Prkdc gene encodes DNA-PKcs which is involved in the immune system, DNA repair and chromosomal integrity. In humans, deficiencies in DNA-PKcs are linked to cancer predisposition. This connection can also be observed in mice models using ionizing radiation as the carcinogenic inducer. In particular, the BALB/c mouse strain is susceptible to mammary cancer after radiation exposure. Subsequent studies have shown that DNA repair is deficient in BALB/c which is attributed to a hypomorphic variant of DNA-PKcs. DNA-PKcs has also been linked to apoptosis because BALB/c is more resistance to ionizing-induced apoptosis in intestinal crypt cells compared to other mouse strains. Furthermore, it has been demonstrated that DNA-PKcs is involved in telomere maintenance. Additional studies have revealed two polymorphisms in Prkdc BALB/c that may be responsible for its DNA-PKcs variant.The relationship between the targeted effects of ionizing radiation and BALB/c has been characterized, i.e. DNA double-strand break repair. However, little has been done on the non-targeted effects of radiation in BALB/c including the bystander effect. The purpose of this research was to study the bystander effect in BALB/c compared to other mouse strains with different levels of DNA-PKcs status. I have found that DNA-PKcs is needed to generate a bystander signal, but not necessary for the reception of the signal. These studies were expanded by determining if the lack of a bystander effect was attributed the PrkdcBALB/c polymorphism in the kinase domain using the LEWES strain. LEWES has the BALB DNA-PKcs allele in the kinase domain and the common allele downstream of the leucine zipper. These results demonstrate that the SNP in the kinase domain influences DNA-PKcs protein levels and DNA repair, but does not affect bystander signaling capabilities. This would suggest that either the polymorphism downstream of the leucine zipper is responsible for the lack of the bystander effect observed in BALB/c or that additional factors influence its phenotype. Because LEWES has decreased DNA-PKcs levels and DNA-repair (not to the same extent as BALB/c), but is able to induce the bystander effect, we can speculate that the lack of bystander signaling in BALB/c may contribute to BALB/c's sensitivity to radiation-induced mammary cancer.born digitaldoctoral dissertationsengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.DNA repairDNA-PKcradiation effectsmolecular biologycellular biologyTextPer the terms of a contractual agreement, all use of this item is limited to the non-commercial use of Colorado State University and its authorized users.