Abstract
The BRCA1 gene product and its stoichiometric binding partner, BARD1, play a vital role in the cellular response to DNA damage. However, how they acquire specific biochemical functions after DNA damage is poorly understood. Following exposure to genotoxic stress, DNA damage-specific interactions were observed between BRCA1/BARD1 and the DNA damage-response proteins, TopBP1 and Mre11/Rad50/NBS1. Two distinct DNA damage-dependent super complexes emerged; their activation was dependent, in part, on the actions of specific checkpoint kinases, and each super complex contributed to a distinctive aspect of the DNA damage response. The results support a new, multifactorial model that describes how genotoxic stress enables BRCA1 to execute a diverse set of DNA damage-response functions.
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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Acid Anhydride Hydrolases
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BRCA1 Protein / genetics
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BRCA1 Protein / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Cycle
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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DNA Damage*
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DNA Repair
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DNA Repair Enzymes / genetics
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DNA Repair Enzymes / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Humans
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MRE11 Homologue Protein
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Binding
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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BRCA1 Protein
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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MRE11 protein, human
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NBN protein, human
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Nuclear Proteins
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TOPBP1 protein, human
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Tumor Suppressor Proteins
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BARD1 protein, human
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Ubiquitin-Protein Ligases
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MRE11 Homologue Protein
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Acid Anhydride Hydrolases
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RAD50 protein, human
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DNA Repair Enzymes