PXD016279-1

PXD016279 is an original dataset announced via ProteomeXchange.

Title	p97/VCP inhibition radiosensitises cancer cells through excessive MRE11-dependent DNA end resection
Description	Cancer cells are under constant proteotoxic stress and have an increased genomic instability. They therefore rely on upregulation of protein homeostasis and the DNA damage response (DDR) for survival. The ubiquitin-dependent ATPase p97 is a central component of the ubiquitin-proteasome degradation system (UPS), involved in both protein homeostasis and DDR. p97 is overexpressed in many tumours and its overexpression correlates with poor prognosis in patients. To explore the concept of cancer cell killing by combined targeting of DDR and proteostasis, we induced DNA damage by ionising radiation (IR) and inhibited proteostasis by CB-5083, a specific small molecule inhibitor of p97, in bladder cancer cell lines and a mouse xenograft model. Combined therapy induced radiosensitivity and supressed xenograft tumour growth. Mechanistically, inactivation of the p97 ATPase activity results in proteotoxic accumulation of the nuclease MRE11 at the sites of IR-induced DNA lesions. This leads to excessive formation of single-stranded DNA (ssDNA), inhibition of HR, reliance on SSA for DSB repair and synthetic lethality after IR exposure in non-homologous end-joining-defective tumour cells such as those in muscle-invasive bladder carcinoma patients
HostingRepository	PRIDE
AnnounceDate	2021-05-19
AnnouncementXML	Submission_2021-05-18_22:32:08.755.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	iolanda Vendrell
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2019-11-14 05:52:32	ID requested
⏵ 1	2021-05-18 22:32:09	announced
2	2024-10-22 05:22:10	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: p97, CB-5083, MRE11, DNA damage, DNA double-strand break repair, homologous recombination, single-strand annealing, ubiquitin, proteasomal degradation, bladder cancer

Anne E Kiltie
contact affiliation	CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
contact email	anne.kiltie@oncology.ox.ac.uk
lab head
iolanda Vendrell
contact affiliation	CRUK-MRC Oxford Institute for Radiation Oncology, Oxford University
contact email	iolanda.vendrell@ndm.ox.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/05/PXD016279

PRIDE project URI

• PRIDE
  1. PXD016279
     1. Label: PRIDE project
     2. Name: p97/VCP inhibition radiosensitises cancer cells through excessive MRE11-dependent DNA end resection