Analysis Tools
mortality/aging
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• in response to 8 Gy whole-body gamma-irradiation, 85.7% of 6-8-week-old homozygous mutant irradiated mice (12/14) die by 32 days post-irradiation (p.i.) versus only 20% of age-matched wild-type irradiated mice (1/5); by comparison, all Parp1tm1Jmdm homozygous mutant mice (6/6) die by by 13 days p.i.
• after 8 Gy whole-body irradiation, homozygous mutant irradiated mice display a dilated duodenum, with more severely shortened villi and increased epithelial crypt degeneration at 6 days p.i. relative to wild-type irradiated mice, suggesting that death is most likely due to acute radiation toxicity in the small intestine epithelium
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cellular
| N |
• in the absence of DNA damage, MEFs obtained from homozygous mutant mice show no defects in cellular proliferation, as revealed by BrdU incorporation assays
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• at 24 hrs after exposure to a sublethal dose of MNU (2 mM), mutant primary MEFs show a notable G2/M arrest (41%) relative to wild-type MEFs (27%), indicating impaired cell cycle progression after DNA base damage
• prolonged G2/M accumulation is accompanied by the acquisition of 8N DNA content (11%) as mutant cells proceed through the next cell cycle
• following MNU treatment, a high proportion of aberrant anaphases, exhibiting one or more lagging (non-segregated) chromosomes and dispersed centromeres, are only observed in mutant MEFs suggesting centromere and kinetochore defects
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• at 9 hrs following i.p. injection with alkylating agent N-methyl-N-nitrosourea (MNU; 75 mg/kg body weight), bone marrow (BM) cells from homozygous mutant mice show a 4-fold increase in the level of SCEs relative to wild-type BM cells
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• following 2 Gy irradiation, BM cells from homozygous mutant irradiated mice exhibit a significant increase in chromatid breaks relative to wild-type BM cells, suggesting a DNA repair deficiency of radiation-induced damage, above all S phase and during G2
• chromatid breaks occur more frequently in centromeric regions in mutant BM cells than in wild-type BM cells
• at 48 hrs after 6 Gy whole-body irradiation, homozygous mutant thymocytes show a high degree of DNA fragmentation that is similar in intensity to that of Parp1tm1Jmdm mutant mice, whereas wild-type thymocytes show little apoptotic death, as revealed by TUNEL staining
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• homozygotes show a severe DNA repair deficiency following exposure to ionizing radiation during G2 and above all S phase in bone marrow cells, with both chromatid breaks and chromatid exchanges significantly increased relative to wild-type mice
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• after 2 Gy irradiation, BM cells from homozygous mutant irradiated mice show a significant increase in chromatid breaks, preferentially in centromeric regions, relative to wild-type irradiated BM cells
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homeostasis/metabolism
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• homozygotes show a severe DNA repair deficiency following exposure to ionizing radiation during G2 and above all S phase in bone marrow cells, with both chromatid breaks and chromatid exchanges significantly increased relative to wild-type mice
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• in response to 8 Gy whole-body gamma-irradiation, 85.7% of 6-8-week-old homozygous mutant irradiated mice (12/14) die by 32 days post-irradiation (p.i.) versus only 20% of age-matched wild-type irradiated mice (1/5); by comparison, all Parp1tm1Jmdm homozygous mutant mice (6/6) die by by 13 days p.i.
• after 8 Gy whole-body irradiation, homozygous mutant irradiated mice display a dilated duodenum, with more severely shortened villi and increased epithelial crypt degeneration at 6 days p.i. relative to wild-type irradiated mice, suggesting that death is most likely due to acute radiation toxicity in the small intestine epithelium
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neoplasm
| N |
• homozygotes are not tumor prone and display no overt phenotypic abnormalities up to 18 months of age
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