PXD040430

PXD040430 is an original dataset announced via ProteomeXchange.

Title	A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant
Description	Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations.
HostingRepository	PRIDE
AnnounceDate	2023-07-18
AnnouncementXML	Submission_2023-07-18_03:58:52.460.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	GraemeBenstead-Hume
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-27 05:20:11	ID requested
⏵ 1	2023-07-18 03:58:52	announced

Dataset with its publication pending

submitter keyword: BRCA1, ovarian cancer, PARP,HUWE1, PARPi

JyotiChoudhary
contact affiliation	Functional Proteomics Institute of Cancer Research
contact email	jyoti.choudhary@icr.ac.uk
lab head
GraemeBenstead-Hume
contact affiliation	ICR
contact email	ghume@icr.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040430
     1. Label: PRIDE project
     2. Name: A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant