PXD037989-1

PXD037989 is an original dataset announced via ProteomeXchange.

Title	Codon Specific Readthrough as a Mechanism of BRCA2 Restoration in Acquired PARP Inhibitor and Chemotherapy Resistance
Description	Alteration of the gene encoding BRCA2, a protein involved in homologous recombination (HR), by missense or nonsense mutations results in sensitivity of a subset of breast and ovarian cancers to platinating agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Conversely, resistance to these agents is often accompanied by secondary BRCA2 mutations that restore a functional protein. Here we characterized clones derived from the BRCA2-mutant ovarian cancer line PEO1 by selection with the PARP inhibitor veliparib. Colony forming assays demonstrated cross-resistance of the resulting clones to multiple PARP inhibitors and cisplatin. Despite the continued presence of a 4965C>A (p.Y1655X) BRCA2 nonsense mutation, HR was restored in the resistant cells. Immunoprecipitation followed by immunoblotting or mass spectrometry demonstrated expression of low levels of BRCA2 protein, including peptides distal to the premature termination codon. Reporter assays demonstrated readthrough selective for the UAG stop codon in the veliparib-resistant clones but not parental PEO1 cells; and mass spectrometry revealed insertion of tyrosine rather than termination in the readthrough product. Mass spectrometry and immunoblotting provided evidence for readthrough of UAGs in additional proteins in the resistant clones. BRCA2 gene interruption 3’ to the stop codon restored sensitivity of the resistant clones to PARP inhibitors and cisplatin, implicating the low level BRCA2 expression in resistance. Accordingly, the present results identify low level readthrough of nonsense codons as a potential mechanism of drug resistance that might need to be considered when assessing the impact of mutations on the biology of cancers.
HostingRepository	PRIDE
AnnounceDate	2025-10-27
AnnouncementXML	Submission_2025-10-26_18:17:38.105.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xinyan Wu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ FT; LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-07 08:50:20	ID requested
⏵ 1	2025-10-26 18:17:39	announced

10.1093/nar/gkaf990;

McGehee CD, Meng XW, Wu X, Correia C, Venkatachalam A, Flatten KS, Peterson KL, Patel AG, Rossman OK, Wong C, Hurley RM, Wagner JM, Schneider PA, Dai H, Poirier GG, Hendrickson AEW, Swisher EM, Pandey A, Li H, Kaufmann SH, Codon specific readthrough as a mechanism of BRCA2 restoration in acquired PARP inhibitor and chemotherapy resistance. Nucleic Acids Res, 53(19):(2025) [pubmed]

submitter keyword: translational readthrough, ovarian cancer,BRCA2

Xinayn Wu
contact affiliation	Mayo Clinic
contact email	wu.xinyan@mayo.edu
lab head
Xinyan Wu
contact affiliation	Mayo Clinic
contact email	wu.xinyan@mayo.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD037989
     1. Label: PRIDE project
     2. Name: Codon Specific Readthrough as a Mechanism of BRCA2 Restoration in Acquired PARP Inhibitor and Chemotherapy Resistance