Abstract
Cell cycle checkpoints play a central role in genomic stability. The human DNA topoisomerase II-binding protein 1 (TopBP1) protein contains eight BRCA1 COOH terminus motifs and shares similarities with Cut5, a yeast checkpoint Rad protein. TopBP1 also shares many features with BRCA1. We report that, when expression of TopBP1 protein is inhibited in BRCA1 mutant cells, mimicking a TopBP1, BRCA1 double-negative condition, the G(2)-M checkpoint is strongly abrogated and apoptosis is increased after ionizing radiation. However, a BRCA1-negative or a TopBP1-negative background resulted in only partial abrogation of the G(2)-M checkpoint. The BRCA1 mutant and TopBP1-reduced condition specifically destroys regulation of the Chk1 kinase but not the Chk2 kinase, suggesting involvement in the ataxia telangiectasia-related pathway. These results indicate that both TopBP1 and BRCA1 specifically regulate the G(2)-M checkpoint, partially compensating each function.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / physiology
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Ataxia Telangiectasia Mutated Proteins
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BRCA1 Protein / physiology*
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Breast Neoplasms / pathology
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Carcinoma / pathology
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Cycle Proteins
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Cell Division / genetics
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Cell Division / physiology
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Checkpoint Kinase 1
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Checkpoint Kinase 2
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DNA-Binding Proteins
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G2 Phase / genetics
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G2 Phase / physiology*
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Genes, BRCA1*
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Genes, cdc*
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Humans
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Metaphase / genetics
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Metaphase / physiology*
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Neoplasm Proteins / physiology
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Nuclear Proteins
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology
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Recombinant Fusion Proteins / physiology
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Signal Transduction / physiology
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Transfection
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / radiation effects
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Tumor Stem Cell Assay
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Tumor Suppressor Proteins
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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Neoplasm Proteins
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Nuclear Proteins
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Oligodeoxyribonucleotides, Antisense
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Recombinant Fusion Proteins
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TOPBP1 protein, human
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Tumor Suppressor Proteins
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Protein Kinases
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Checkpoint Kinase 2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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CHEK2 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases