Abstract
The BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. The BH3-only members of this family act as sentinels, interconnecting specific death signals to the core apoptotic pathway. Our previous data demonstrated a role for BH3-only BID in maintaining myeloid homeostasis and suppressing leukemogenesis. In the absence of Bid, mice accumulate chromosomal aberrations and develop a fatal myeloproliferative disorder resembling chronic myelomonocytic leukemia. Here, we describe a role for BID in preserving genomic integrity that places BID at an early point in the path to determine the fate of a cell. We show that BID plays an unexpected role in the intra-S phase checkpoint downstream of DNA damage distinct from its proapoptotic function. We further demonstrate that this role is mediated through BID phosphorylation by the DNA-damage kinase ATM. These results establish a link between proapoptotic Bid and the DNA-damage response.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics*
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Ataxia Telangiectasia Mutated Proteins
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BH3 Interacting Domain Death Agonist Protein
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Transformed
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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DNA Damage / drug effects
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DNA Damage / genetics*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Female
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Genes, cdc / drug effects
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Genes, cdc / physiology
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Genomic Instability / genetics
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Leukemia, Myelomonocytic, Chronic / genetics
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Leukemia, Myelomonocytic, Chronic / metabolism
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Male
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Mice
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Mice, Knockout
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Mutagens / pharmacology
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Myeloid Progenitor Cells / metabolism*
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NIH 3T3 Cells
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary / genetics
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S Phase / genetics
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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BH3 Interacting Domain Death Agonist Protein
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Bid protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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Mutagens
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Tumor Suppressor Proteins
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases