The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development.
Cells of metazoan organisms respond to DNA damage by arresting their cell cycle to repair DNA, or they undergo apoptosis. Two protein kinases, ataxia-telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR), are sensors for DNA damage. In humans, ATM is mutated in patients with ataxia-telangiectasia (A-T), resulting in hypersensitivity to ionizing radiation (IR) and increased cancer susceptibility. Cells from A-T patients exhibit chromosome aberrations and excessive spontaneous apoptosis. We used Drosophila as a model system to study ATM function. Previous studies suggest that mei-41 corresponds to ATM in Drosophila; however, it appears that mei-41 is probably the ATR ortholog. Unlike mei-41 mutants, flies deficient for the true ATM ortholog, dATM, die as pupae or eclose with eye and wing abnormalities. Developing larval discs exhibit substantially increased spontaneous chromosomal telomere fusions and p53-dependent apoptosis. These developmental phenotypes are unique to dATM, and both dATM and mei-41 have temporally distinct roles in G2 arrest after IR. Thus, ATM and ATR orthologs are required for different functions in Drosophila; the developmental defects resulting from absence of dATM suggest an important role in mediating a protective checkpoint against DNA damage arising during normal cell proliferation and differentiation.
Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th St., Charlestown, MA 02129, USA.
Young-Han
YH
Song
Gladys
G
Mirey
Martha
M
Betson
Daniel A
DA
Haber
Jeffrey
J
Settleman
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D004330:Drosophila / Q000196:embryology / Q000378:metabolism / Q000528:radiation effects*; D029721:Drosophila Proteins / Q000235:genetics; D005123:Eye / Q000473:pathology; D005260:Female; D005298:Fertility / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020287:In Situ Nick-End Labeling; D007814:Larva / Q000378:metabolism / Q000528:radiation effects; D008855:Microscopy, Electron, Scanning; D008938:Mitosis / Q000528:radiation effects*; D010802:Phylogeny; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins; D014921:Wings, Animal / Q000473:pathology; D014965:X-Rays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C444435:Mei-41 protein, Drosophila; D017346:Protein Serine-Threonine Kinases