PXD052191

PXD052191 is an original dataset announced via ProteomeXchange.

Title	PARP1 auto-modification promotes faithful Okazaki fragment processing and limits replication fork speed
Description	Poly(ADP-ribose) polymerase (PARP) inhibitors have proven their efficacy for treating tumors defective in homologous recombination via synthetic lethality. In response to DNA breaks, PARP1 is the primary ADP-ribosylation writer, modifying itself (auto-modification) and other proteins to facilitate repair. However, enzymatic inhibition blocks both processes, making it difficult to dissect their distinct functional roles. Using proteomics and site-directed mutagenesis, we identified a PARP1 mutant deficient in auto-modification, yet it retains catalytic activity. This separation-of-function mutant revealed that PARP1 auto-modification slows DNA replication fork progression but is dispensable for repair factor recruitment. Instead, auto-modification promotes the timely release of PARP1 at DNA break sites and prevents the formation of replication stress. Simultaneous inhibition of FEN1 and loss of PARP1 auto-modification gives rise to synthetic lethality, implicating auto-modification in Okazaki fragment processing. Our results demonstrate that trapping of PARP at DNA breaks impedes repair factor accessibility, constituting an important dimension of PARP-inhibitor-driven cytotoxicity.
HostingRepository	PRIDE
AnnounceDate	2025-10-03
AnnouncementXML	Submission_2025-10-02_16:41:59.733.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonas Elsborg
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Xenopus laevis (African clawed frog); NCBI TaxID: NEWT:8355;
ModificationList	adenosine diphosphoribosyl (ADP-ribosyl) modified residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Astral; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-10 19:49:13	ID requested
⏵ 1	2025-10-02 16:42:00	announced

10.1016/J.MOLCEL.2025.09.006;

submitter keyword: Okazaki fragment processing,PARP1, DNA repair, Af1521 macrodomain, ADP-ribosylation, Xenopus egg extract, auto-modification, DNA replication

Michael Lund
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
contact email	michael.lund.nielsen@cpr.ku.dk
lab head
Jonas Elsborg
contact affiliation	NNF Center for Protein Research
contact email	jonas.elsborg@cpr.ku.dk
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/2025/10/PXD052191

PRIDE project URI

• PRIDE
  1. PXD052191
     1. Label: PRIDE project
     2. Name: PARP1 auto-modification promotes faithful Okazaki fragment processing and limits replication fork speed