We previously demonstrated strain differences in susceptibility to radiation-induced mammary cancer and radiation- induced cytogenetic instability between sensitive BALB/cByJ, and resistant C57BL/6ByJ mice and provided evidence that such susceptibility differences were heritable traits. Sequence analysis of cDNA from these strains indicate two polymorphisms unique to the BALB/c mouse. Studies in the two strains, F1 hybrids, and in backcross animals have demonstrated a significant association between susceptibility to radiation-induced cytogenetic instability and Prkdc, the gene encoding the catalytic subunit of DNA dependent protein kinase (DNA PKcs). Mice homozygous for the BALB/c Prkdc allele (Prkdc BALs'c) are also deficient in the post-irradiation repair of double strand breaks, showed a reduced kinase activity, and western analyses showed a reduced intensity of signal for DNA-PKcs. Since the repair deficiency, reduced western signal intensity, reduced kinase activity, and the presence of these two polymorphisms are all significantly associated with increased susceptibility to radiation-induced cytogenetic instability, we now propose to examine the genetic linkage between this locus and susceptibility to radiation-induced mammary cancer, and to more directly illucidate the role of Prkdc BALB/cin radiation-induced instability and mammary cancer. We have now also demonstrated that irradiation of mammary cells from BALB/c as well as SCID, which have a truncating mutation of Prkdc, results in fusions between telomeres and radiation-induced double strand breaks (DSB) presumably as a result of a defect in the function of DNA- PKcs as an important element in telomere maintenance. Specifically, the aims of this project are to: 1) directly determine the functional consequence of polymorphorisms in PrkdcBALB; 2) determine the role of Prkdc BALB in susceptibility to radiation-induced mammary cancer; 3) determine the contribution of telomere dysfunction in radiation-induced cytogenetic instability and mammary cancer.
| Fabre, Kristin M; Ramaiah, Lila; Dregalla, Ryan C et al. (2011) Murine Prkdc polymorphisms impact DNA-PKcs function. Radiat Res 175:493-500 |
| Williams, Eli S; Klingler, Rebekah; Ponnaiya, Brian et al. (2009) Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence. Cancer Res 69:2100-7 |
| Carsten, Ronald E; Bachand, Annette M; Bailey, Susan M et al. (2008) Resveratrol reduces radiation-induced chromosome aberration frequencies in mouse bone marrow cells. Radiat Res 169:633-8 |
| Hagelstrom, R T; Askin, K F; Williams, A J et al. (2008) DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals. Oncogene 27:6761-9 |
| Williams, Eli S; Stap, Jan; Essers, Jeroen et al. (2007) DNA double-strand breaks are not sufficient to initiate recruitment of TRF2. Nat Genet 39:696-8;author reply 698-9 |
| Bailey, Susan M; Murnane, John P (2006) Telomeres, chromosome instability and cancer. Nucleic Acids Res 34:2408-17 |
| Bailey, Susan M; Brenneman, Mark A; Goodwin, Edwin H (2004) Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. Nucleic Acids Res 32:3743-51 |
| Bailey, Susan M; Cornforth, Michael N; Ullrich, Robert L et al. (2004) Dysfunctional mammalian telomeres join with DNA double-strand breaks. DNA Repair (Amst) 3:349-57 |
| Pati, Debananda; Haddad, Bassem R; Haegele, Albert et al. (2004) Hormone-induced chromosomal instability in p53-null mammary epithelium. Cancer Res 64:5608-16 |
| Bailey, S M; Goodwin, E H (2004) DNA and telomeres: beginnings and endings. Cytogenet Genome Res 104:109-15 |
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