Abstract
Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis
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CRISPR-Cas Systems
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Cell Line, Tumor
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DNA Breaks, Double-Stranded
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DNA Replication
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DNA, Neoplasm / metabolism
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Deoxycytidine Monophosphate / analogs & derivatives
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Deoxycytidine Monophosphate / metabolism
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Deoxycytidine Monophosphate / pharmacology
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Deoxyuracil Nucleotides / metabolism
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Drug Resistance, Neoplasm
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Genes, BRCA1
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Humans
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Hydrolysis
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N-Glycosyl Hydrolases / antagonists & inhibitors*
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N-Glycosyl Hydrolases / genetics
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N-Glycosyl Hydrolases / metabolism*
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Phthalazines / pharmacology
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Piperazines / pharmacology
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Synthetic Lethal Mutations
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Thymidine / analogs & derivatives
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Thymidine / antagonists & inhibitors
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Thymidine / metabolism
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Thymidine / pharmacology
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Uracil-DNA Glycosidase / metabolism
Substances
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Antineoplastic Agents
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DNA, Neoplasm
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Deoxyuracil Nucleotides
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Phthalazines
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Piperazines
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Poly(ADP-ribose) Polymerase Inhibitors
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Proto-Oncogene Proteins
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Deoxycytidine Monophosphate
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5-hydroxymethyl-2'-deoxyuridine
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5-hydroxymethyldeoxycytidine monophosphate
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Poly(ADP-ribose) Polymerases
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DNPH1 protein, human
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N-Glycosyl Hydrolases
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SMUG1 protein, human
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Uracil-DNA Glycosidase
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Thymidine
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olaparib