1. Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA -deficient cells to PARP inhibitors.
- Author
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Fugger K, Bajrami I, Silva Dos Santos M, Young SJ, Kunzelmann S, Kelly G, Hewitt G, Patel H, Goldstone R, Carell T, Boulton SJ, MacRae J, Taylor IA, and West SC
- Subjects
- Apoptosis, CRISPR-Cas Systems, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Replication, DNA, Neoplasm metabolism, Deoxycytidine Monophosphate analogs & derivatives, Deoxycytidine Monophosphate metabolism, Deoxycytidine Monophosphate pharmacology, Deoxyuracil Nucleotides metabolism, Drug Resistance, Neoplasm, Genes, BRCA1, Humans, Hydrolysis, N-Glycosyl Hydrolases genetics, Phthalazines pharmacology, Piperazines pharmacology, Poly(ADP-ribose) Polymerases metabolism, Proto-Oncogene Proteins genetics, Synthetic Lethal Mutations, Thymidine analogs & derivatives, Thymidine antagonists & inhibitors, Thymidine metabolism, Thymidine pharmacology, Uracil-DNA Glycosidase metabolism, Antineoplastic Agents pharmacology, N-Glycosyl Hydrolases antagonists & inhibitors, N-Glycosyl Hydrolases metabolism, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins metabolism
- 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.)
- Published
- 2021
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