PXD067930

PXD067930 is an original dataset announced via ProteomeXchange.

Title	Tumor cell intrinsic dsRNA innate immune response triggered by PARP inhibitor is compromised in BRCA1 deficient breast cancer by repressing IRF3
Description	Poly (ADP-ribose) polymerase 1 (PARP1) inhibition represents promising targeted therapy for BRCA deficient cancer patients based on synthetic lethality theory. Recent evidence shows that efficacy of DNA damage drugs depends on two aspects, DNA repair signaling and immune response. Applying a functional proteomics approach, we find that the function of spliceosome is perturbed by PARP inhibitors via enhancing interaction between PARP1 and SF3B1, a key factor of spliceosome. We demonstrate that differential alternative spliced mRNA and accumulation of double strand RNA (dsRNA) are induced by perturbation of spliceosome upon PARP inhibitors treatment, resulting in triggering dsRNA antiviral mimicry innate immune response. Moreover, we identify a novel function of BRCA1, through which BRCA1 regulates innate immune response leading to compromising of the innate immune signaling by downregulation of IRF3 in BRCA1 deficient breast cancer cells, which reduces the sensitivity to PARP inhibitors and causes intrinsic resistance. Polyinosinic-polycytidylic acid (poly(I:C)) is a dsRNA synthetic analog sensitizing PARP inhibitors through further triggering dsRNA signaling. Finally, we show that the combination of PARP inhibitors and poly(I:C) enhances antitumor efficiency in vivo. Overall, our study reveals BRCA1 deficiency impedes tumor cell intrinsic innate immune response, inducing intrinsic resistance to PARP inhibitors that can be overcome when poly(I:C) is combined.
HostingRepository	iProX
AnnounceDate	2025-09-01
AnnouncementXML	Submission_2026-08-31_00:59:06.426.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Cuiting Zhang
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-01 01:34:22	ID requested
⏵ 1	2026-08-31 00:59:06	announced

Dataset with its publication pending

submitter keyword: PARP inhibitor, limited proteolysis-mass spectrometry, innate immune response, BRCA1 deficiency, IRF3, poly(I:C)

Chuxia Deng
contact affiliation	University of Macau
contact email	cxdeng@um.edu.mo
lab head
Cuiting Zhang
contact affiliation	University of Macau
contact email	yc07631@connect.um.edu.mo
dataset submitter

iProX dataset URI