c-Abl tyrosine kinase is not essential for ataxia telangiectasia mutated functions in chromosomal maintenance.
c-Abl is activated by DNA damage in an ataxia telangiectasia mutated (ATM)-dependent manner and plays important roles in growth arrest and apoptosis induced by DNA damage. c-Abl also interacts physically and functionally with Rad51, a key molecule in homologous recombinational (HR) DNA repair. To study further the roles of c-Abl in HR DNA repair, we generated c-Abl(-/-) and ATM(-/-)/c-Abl(-/-) mutant cell lines from a chicken B lymphocyte DT40 cell line, comparing the phenotypes of these mutants to those of ATM(-/-) DT40 cells that we had created previously. We found that the time course of radiation-induced Rad51 focus formation is abnormal in ATM(-/-) DT40 cells, consistent with the observation that ATM(-/-) DT40 cells display hypersensitivity to ionizing radiation and highly elevated frequencies of both spontaneous and radiation-induced chromosomal aberrations. In contrast, c-Abl(-/-) cells did not show these ATM-related defects in their cellular response to radiation, nor did the disruption of c-Abl in ATM(-/-) DT40 cells exacerbate these ATM-related defects. However, c-Abl(-/-) DT40 cells, but not ATM(-/-) DT40 cells, were resistant to radiation-induced apoptosis, indicating an important role for c-Abl in this cellular response to ionizing radiation. These results therefore indicate that, although ATM plays an important role in genome maintenance, c-Abl is not essential for this ATM function. These findings suggest that c-Abl and ATM play important roles in the maintenance of the cell homeostasis in response to DNA damage that are, at least in part, independent.
Takao
N
N
Department of Molecular Pathology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
Mori
R
R
Kato
H
H
Shinohara
A
A
Yamamoto
K i
Ki
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D030161:Avian Proteins; D001402:B-Lymphocytes; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival; D002645:Chickens; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D016313:Genes, abl; D007621:Karyotyping; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051135:Rad51 Recombinase; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins
D030161:Avian Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C495150:RAD51 protein, Gallus gallus; D051135:Rad51 Recombinase