| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Repair of DNA damage is essential for the maintenance of genomic integrity. In mammalian cells, DNA polymerase β (Polβ) has been implicated in base excision repair. However, the physiological significance of the enzyme in the body remains unclear. We have previously shown that Polβ-deficient mice die of a respiratory failure immediately after the birth and that the mice exhibit extensive apoptotic cell death in the developing nervous systems. The cell death occurs in newly generated postmitotic neuronal cells rather than in mitotic progenitor cells and is closely linked to the onset and cessation of neurogenesis. In this study, by generating double knockout mice with mice deficient in ATM, scid, or p53, we examined potential roles of these proteins in the induction of neural cell death. These proteins are implicated in DNA damage sensing, checkpoint control in the cell cycle and apoptosis. Polβ-/ -Atm-/-and Polβ-/-scid mice exhibited embryonic lethal at the early developmental stage compared with Polβ-/-mice. In contrast, p53 deficiency could completely rescue neuronal apoptosis in Polβ-null mice, indication that p53 is required for the induction of apoptosis found in the Polβ-deficient developing nervous system. Unexpectedly, Polβ-/-p53-/- mice died after the birth, showing abnormalities of the nervous system as observed in Polβ-/-mice. These results suggest that Polβ plays a critical role in the differentiation of postmitotic cells into a mature neuron. On the other hand, we examined the effect of Polβ deficiency on mutations in tissues using intercrosses with HITEC mice. We found that embryonic brains of Polβ-null mice show a decreased mutant frequency compared with wild-type mice, although no difference was found in kidney, liver and thymus.
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