PXD014836

PXD014836 is an original dataset announced via ProteomeXchange.

Title	Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation
Description	PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (i.e., PARP1 catalytic inhibition vs. PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is incompletely understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib (1) results in highly efficient and specific PARP1 degradation. iRucaparib blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated PARylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib protects muscle cells and primary cardiomyocytes from DNA damage-induced energy crisis and cell death. In summary, these compounds represent “non-trapping” PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.
HostingRepository	PRIDE
AnnounceDate	2019-11-08
AnnouncementXML	Submission_2019-11-08_00:44:26.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shuai Wang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-31 01:21:31	ID requested
1	2019-08-01 01:23:23	announced
⏵ 2	2019-11-08 00:44:40	announced	2019-11-08: Updated publication reference for PubMed record(s): 31659317.

Wang S, Han L, Han J, Li P, Ding Q, Zhang QJ, Liu ZP, Chen C, Yu Y, Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation. Nat Chem Biol, 15(12):1223-1231(2019) [pubmed]

submitter keyword: iRucaparib-TP3, PARP1 degradation, HeLa cell

Yonghao Yu
contact affiliation	Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas
contact email	yonghao.yu@UTSouthwestern.edu
lab head
Shuai Wang
contact affiliation	UT Southwestern Medical Center
contact email	shuai.wang@UTSouthwestern.edu
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/2019/08/PXD014836

PRIDE project URI

• PRIDE
  1. PXD014836
     1. Label: PRIDE project
     2. Name: Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation