PXD061071-1

PXD061071 is an original dataset announced via ProteomeXchange.

Title	NASP modulates histone turnover to drive PARP inhibitor resistance
Description	PARP inhibitors (PARPi) present a remarkable advance in the treatment of patients with homologous recombination (HR)-deficient tumors1-3, however resistance remains a challenge due to genomic instability4,5. While most research has focused on the downstream consequences of PARPi exposure to tackle resistance, the immediate impact of PARP inhibition on the chromatin environment and its contribution to PARPi toxicity remains elusive. Here, we show that PARP inhibition induces histone release from the chromatin. This presents a vulnerability of PARPi-resistant cancer cells, which are addicted to histone homeostasis mechanisms to sustain elevated DNA replication rates and survival. Through functional genetic screens, we identified NASP as a key factor in maintaining the stability of evicted histones via its TPR motifs. NASP loss renders tumor cells hypersensitive to PARPi treatment in vitro and in vivo, impairs replication fork progression and elevates levels of replication-associated DNA damage. Moreover, NASP acts together with the INO80 complex and the chaperoning activity of PARP1 to ensure efficient histone turnover and prevent the accumulation of lethal DNA damage following PARPi exposure. Collectively, our work reports on histone eviction as an immediate cellular response to PARPi treatment and provides a promising avenue for targeting histone supply pathways to overcome PARPi resistance.
HostingRepository	PRIDE
AnnounceDate	2025-07-29
AnnouncementXML	Submission_2025-07-29_10:48:53.638.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Liesbeth Hoekman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-21 16:31:11	ID requested
⏵ 1	2025-07-29 10:48:54	announced

Dataset with its publication pending

submitter keyword: LC-MSMS,NASP, PARP inhibitor, Human

Onno Bleijerveld
contact affiliation	Mass Spectrometry/Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands
contact email	o.bleijerveld@nki.nl
lab head
Liesbeth Hoekman
contact affiliation	The Netherlands Cancer Institute, Amsterdam, The Netherlands.
contact email	l.hoekman@nki.nl
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/2025/07/PXD061071

PRIDE project URI

• PRIDE
  1. PXD061071
     1. Label: PRIDE project
     2. Name: NASP modulates histone turnover to drive PARP inhibitor resistance