@article{ec44d958d64b4c329fc45071ba749583,
title = "Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors",
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.",
author = "Kasper Fugger and Ilirjana Bajrami and {Dos Santos}, {Mariana Silva} and Young, {Sarah Jane} and Simone Kunzelmann and Geoff Kelly and Graeme Hewitt and Harshil Patel and Robert Goldstone and Thomas Carell and Boulton, {Simon J.} and James MacRae and Taylor, {Ian A.} and West, {Stephen C.}",
note = "Funding Information: This work was supported by the Francis Crick Institute grant FC0010212 (S.C.W.; the Francis Crick Institute receives core funding from Cancer Research UK, the Medical Research Council, and the Wellcome Trust); the European Research Council grant ERC-ADG-666400 (S.C.W.); the Louis-Jeantet Foundation (S.C.W.); the Benzon Foundation (K.F.); and the Lundbeck Foundation (K.F.). Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",
year = "2021",
month = apr,
day = "9",
doi = "10.1126/science.abb4542",
language = "English",
volume = "372",
pages = "156--165",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6538",
}