Ataxia-Telangiectasia: Defective in a P53-Dependent Signal Transduction Pathway
Damage to DNA in proliferating cells results in alterations of progression through the cell cycle (e.g. Tolmach et al, 1977; Painter and Young, 1980; Lau and Pardee, 1982; Weinert and Hartwell, 1988; Kaufmann et al, 1991; O’Connor et al, 1992). Such cell cycle “checkpoints” appear to be active cellular responses which permit optimal repair of DNA damage so that the cell will not replicate a damaged DNA template (G1 arrest) nor segregate damaged chromosomes (G2 arrest). Defects in these checkpoints are thought to contribute to decreased cell survival and increased propagatable genetic abnormalities following DNA damage (Hartwell and Weinert, 1989). One consequence of failing to repair DNA damage prior to replicative DNA synthesis is that mutagenic lesions could be fixed and propagated and could thus contribute to the genomic changes which result in neoplastic transformation. Abnormalities in the RAD9 gene in yeast result in a defect in the G2 arrest following ionizing irradiation — such mutant yeast exhibit increased sensitivity and increased genetic abnormalities following exposure to ionizing radiation (Weinert and Hartwell, 1988; Hartwell and Weinert, 1989). However, little has been clarified about the molecular and genetic controls of these checkpoints in mammalian cells.
KeywordsCell Cycle Checkpoint Ataxia Telangiectasia Nijmegen Breakage Syndrome GADD45 Gene Diphosphate Ribose
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