PXD071389-1

PXD071389 is an original dataset announced via ProteomeXchange.

Title	Nucleophagy removes cytotoxic trapped PARP1
Description	Poly (ADP-ribose) polymerase inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HRR)-deficient cancers by causing PARP1 to become trapped on chromatin, resulting in irreparable replication-associated DNA damage. Cancer cells commonly develop resistance to PARPi, with a recently proposed mechanism being the clearance of trapped PARP1 from chromatin, yet details surrounding this process remain unclear. PARPi treatment causes increased autophagy flux, whilst autophagy inhibition can hypersensitise cells to PARPi. With selective autophagy of nuclear substrates (nucleophagy) shown, we wanted to explore if this occurs during DNA damage repair by the clearance of trapped PARP1. We used various biochemical, cell biological and live imaging-based assays, demonstrating that trapped PARP1 is processed by nucleophagy. We identified that nucleophagy of trapped PARP1 is orchestrated by selective autophagy receptor TEX264 and its partner protein p97/VCP. TEX264 directly interacts with trapped PARP1, then bridges PARP1 to autophagosomal resident protein LC3 for processing via autophagy. Impeding this process, either chemically or genetically, heightened PARP1 trapping, leading to accumulation of protein aggregates, replication-associated DNA damage and cell lethality, re-sensitising PARPi-resistant cells to various PARPi. In conclusion, we show that nucleophagy acts in a cytoprotective manner to directly target PARPi-induced trapped PARP1 for degradation.
HostingRepository	PRIDE
AnnounceDate	2026-04-15
AnnouncementXML	Submission_2026-04-15_03:29:05.924.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	andrea pierangelini
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-29 14:21:49	ID requested
⏵ 1	2026-04-15 03:29:06	announced

Dataset with its publication pending

ProteomeXchange project tag: Hydrogen Deuterium Exchange (HDX-MS)

submitter keyword: HDX-MS

Darragh O'Brien
contact affiliation	Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK
contact email	darragh.obrien@ndm.ox.ac.uk
lab head
andrea pierangelini
contact affiliation	Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK
contact email	andrea.pierangelini@cmd.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/2026/04/PXD071389

PRIDE project URI

• PRIDE
  1. PXD071389
     1. Label: PRIDE project
     2. Name: Nucleophagy removes cytotoxic trapped PARP1