Abstract
The Fanconi anemia (FA) pathway maintains genomic stability in replicating cells. Some sporadic breast, ovarian, pancreatic, and hematological tumors are deficient in FA pathway function, resulting in sensitivity to DNA-damaging agents. FA pathway dysfunction in these tumors may result in hyperdependence on alternative DNA repair pathways that could be targeted as a treatment strategy. We used a high-throughput siRNA screening approach that identified ataxia telangiectasia mutated (ATM) as a critical kinase for FA pathway-deficient human fibroblasts. Human fibroblasts and murine embryonic fibroblasts deficient for the FA pathway were observed to have constitutive ATM activation and Fancg(-/-)Atm(-/-) mice were found to be nonviable. Abrogation of ATM function in FA pathway-deficient cells resulted in DNA breakage, cell cycle arrest, and apoptotic cell death. Moreover, Fanconi anemia complementation group G- (FANCG-) and FANCC-deficient pancreatic tumor lines were more sensitive to the ATM inhibitor KU-55933 than isogenic corrected lines. These data suggest that ATM and FA genes function in parallel and compensatory roles to maintain genomic integrity and cell viability. Pharmaceutical inhibition of ATM may have a role in the treatment of FA pathway-deficient human cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / genetics*
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Cell Line, Transformed
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Cell Line, Tumor
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Cells, Cultured
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DNA Damage
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics*
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Fanconi Anemia / genetics
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Fanconi Anemia / metabolism*
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Fanconi Anemia Complementation Group C Protein / deficiency
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Fanconi Anemia Complementation Group C Protein / genetics
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Fanconi Anemia Complementation Group C Protein / physiology*
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Fanconi Anemia Complementation Group G Protein / deficiency*
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Fanconi Anemia Complementation Group G Protein / genetics*
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Fanconi Anemia Complementation Group G Protein / physiology
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HeLa Cells
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Humans
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Mice
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Mice, Knockout
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics*
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Signal Transduction / genetics*
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Tumor Suppressor Proteins / antagonists & inhibitors*
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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FANCG protein, human
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Fanconi Anemia Complementation Group C Protein
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Fanconi Anemia Complementation Group G Protein
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Tumor Suppressor Proteins
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases