PXD069001

PXD069001 is an original dataset announced via ProteomeXchange.

Title	ISG15 promotes PARP inhibitor resistance in BRCA1-deficient cells by facilitating DNA replication and repair
Description	The use of poly(ADP-ribose) polymerase inhibitors (PARPi) has proven largely successful in targeting BRCA1/2-mutated tumours. However, the emergence of PARPi-resistant disease can reduce the efficacy of this treatment, posing significant challenges in the clinic. Here, we use multiple models of BRCA1-/- cells and patient-derived xenografts (PDXs) that have been treated with PARPi until they no longer respond to the drug, to characterise genomic and transcriptomic alterations specific to PARPi resistance. We find that abrogation of TP53BP1 expression occurs spontaneously during prolonged PARPi treatment and is caused by genomic deletions and promoter methylation. Moreover, genes upregulated in PARPi-resistant cells and tumours predominantly consist of innate immune response genes, including ISG15 and factors of the ISGylation machinery. We demonstrate that ISG15 inhibition re-sensitises PARPi-resistant cells to the drug exogenous and, conversely, that ISG15 overexpression in BRCA1-/- cells triggers PARPi resistance. Mechanistically, ISG15 is required in BRCA1-/- PARPi-resistant cells for replication fork progression and for DNA double-strand break (DSB) repair via homologous recombination (HR). Our results indicate that complex ISG15 interactions with DNA replication/repair factors can drive PARPi resistance in BRCA1-deficient cancer cells and that targeting ISG15 has the potential to overcome PARPi resistance.
HostingRepository	PRIDE
AnnounceDate	2026-08-18
AnnouncementXML	Submission_2026-08-18_07:18:11.397.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Adan Pinto-Fernandez
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-30 07:07:07	ID requested
⏵ 1	2026-08-18 07:18:11	announced

Dataset with its publication pending

submitter keyword: DNA Damage, DNA Replication, Cancer, PARP,ISG15, BRCA

Adan Pinto-Fernandez
contact affiliation	COI-NDM
contact email	adan.pintofernandez@ndm.ox.ac.uk
lab head
Adan Pinto-Fernandez
contact affiliation	University of Oxford
contact email	adan.pintofernandez@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069001
     1. Label: PRIDE project
     2. Name: ISG15 promotes PARP inhibitor resistance in BRCA1-deficient cells by facilitating DNA replication and repair