Abstract
Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
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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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Carrier Proteins / genetics
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Cell Line, Tumor
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Cisplatin / pharmacology
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DNA / biosynthesis
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DNA / metabolism
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DNA Breaks, Double-Stranded
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DNA Damage / drug effects
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DNA Damage / genetics
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DNA Helicases / genetics
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DNA Repair / drug effects
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DNA Repair / genetics
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DNA Repair Enzymes / antagonists & inhibitors
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DNA Repair Enzymes / metabolism
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DNA Replication / drug effects
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DNA Replication / physiology*
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Embryonic Stem Cells / drug effects
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Embryonic Stem Cells / metabolism
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Female
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Gene Deletion*
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Genes, BRCA1*
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Genes, BRCA2*
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Homologous Recombination
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MRE11 Homologue Protein
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Mice
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Neoplasms / genetics
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Neoplasms / pathology*
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Nuclear Proteins / deficiency*
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Nuclear Proteins / genetics
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
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Poly(ADP-ribose) Polymerases / genetics
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Mre11a protein, mouse
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Nuclear Proteins
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Paxip1 protein, mouse
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Poly(ADP-ribose) Polymerase Inhibitors
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DNA
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Parp1 protein, mouse
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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MRE11 Homologue Protein
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Mi-2beta protein, mouse
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DNA Helicases
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DNA Repair Enzymes
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Cisplatin