The Effects of DNA-PKcs Deficit on Cellular Senescence and Intrauterine Growth in Canine Models of Severe Combined Immunodeficiency
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DNA double strand breaks (DSBs) are among the most dangerous forms of DNA damage and their repair is essential to maintain genome integrity. Umepaired or misrepaired DSBs can lead to chromosome aberrations, apoptosis, replicative senescence, and tumorigenesis. Non-homologous end-joining, a process which requires the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), is the main mechanism ofDSB repair during most stages of the cell cycle and in V(D)J recombination, the process that results in the production of antigen-specific B and T lymphocytes. DNA-PKcs deficiency resulting in severe combined immunodeficiency (SCID) has been reported in mice, Arabian horses, and Jack Russell terriers. This study investigates the relationship between DNA-PKcs deficiency and cellular senescence. Cell lines derived from fetal puppies, juveniles, and adults were stained with a beta-galactosidase marker for replicative senescence. As senescence may also affect the growth of cell cultures and tissues, the effect ofDNA-PKcs deficiency on cell and fetal growth was analyzed with growth curves and fetal measurements obtained by sonography. DNA-PKcs -/- fetuses were found to display increased cell senescence as well as early growth deficiencies compared to their unaffected heterozygous littermates. Adult canine fibroblasts did not show a noticeable difference in growth and senescence between SCID and non-SCID individuals. These results confirm the importance of DNA-PKcs in maintaining chromosomal stability, especially during periods of high cell growth and division. This study contributes to the ongoing investigation of how DNA-PKcs and the NHEJ pathway function in maintaining the growth and long-term health of many mammalian species.