Abstract
'BRCAness' is a term used to describe cancer cells that behave similarly to tumors with BRCA1 or BRCA2 mutations. The BRCAness phenotype is associated with hypersensitivity to chemotherapy agents including PARP inhibitors, which are a promising class of recently-licensed anti-cancer treatments. This hypersensitivity arises because of a deficiency in the homologous recombination (HR) pathway for DNA double-strand break repair. To gain further insight into how genetic modifiers of HR contribute to the BRCAness phenotype, we created a new mouse model of BRCAness by generating mice that are deficient in BLM helicase and the Exo1 exonuclease, which are involved in the early stages of HR. We find that cells lacking BLM and Exo1 exhibit a BRCAness phenotype, with diminished HR, and hypersensitivity to PARP inhibitors. We further tested how 53BP1, an important regulator of HR, affects repair efficiency in our BRCAness model. We find that deletion of 53BP1 can relieve several of the repair deficiencies observed in cells lacking BLM and Exo1, just as it does in cells lacking BRCA1. These results substantiate the importance of BRCAness as a concept for classification of cancer cases, and further clarify the role of 53BP1 in regulation of DNA repair pathway choice in mammalian cells.
Keywords:
53BP1; DNA Repair; G2M checkpoint; ionizing radiation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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B-Lymphocytes / radiation effects
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BRCA1 Protein / genetics
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BRCA1 Protein / metabolism
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BRCA2 Protein / genetics
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BRCA2 Protein / metabolism
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Cell Proliferation / drug effects
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Cell Proliferation / radiation effects
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DNA / genetics
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DNA / metabolism
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DNA Breaks, Double-Stranded / radiation effects
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DNA Repair / drug effects*
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DNA Repair Enzymes / deficiency
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DNA Repair Enzymes / genetics*
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Exodeoxyribonucleases / deficiency
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Exodeoxyribonucleases / genetics*
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G2 Phase Cell Cycle Checkpoints / drug effects
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G2 Phase Cell Cycle Checkpoints / genetics*
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G2 Phase Cell Cycle Checkpoints / radiation effects
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Gamma Rays
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Gene Deletion
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Gene Expression
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Genomic Instability
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Humans
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Mice
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Mice, Knockout
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
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Primary Cell Culture
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RecQ Helicases / deficiency
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RecQ Helicases / genetics*
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Sister Chromatid Exchange
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Tumor Suppressor p53-Binding Protein 1 / deficiency
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Tumor Suppressor p53-Binding Protein 1 / genetics*
Substances
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BRCA1 Protein
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BRCA2 Protein
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BRCA2 protein, mouse
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Brca1 protein, mouse
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Poly(ADP-ribose) Polymerase Inhibitors
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Trp53bp1 protein, mouse
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Tumor Suppressor p53-Binding Protein 1
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DNA
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Exo1 protein, mouse
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Exodeoxyribonucleases
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Bloom syndrome protein
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RecQ Helicases
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DNA Repair Enzymes