PXD043522

PXD043522 is an original dataset announced via ProteomeXchange.

Title	Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity
Description	Recent studies have highlighted the critical role of metabolism in the response to DNA damage. However, the precise metabolic interactions that are set in motion to tune this fundamental process remain largely unknown. In this study, we investigated the role of nuclear metabolism in the DNA damage response using triple-negative breast cancer as a model. By comparing the chromatin-associated proteome of different breast cancer subtypes, we observed that the purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched in the chromatin of triple-negative breast cancer cells, which are often prone to DNA damage accumulation. Downregulation, depletion, or inhibition of IMPDH2 leads to accumulation of DNA damage. IMPDH2 chromatin localization is DNA damage dose dependent and happens at a late stage of the DNA damage repair. On chromatin, IMPDH2 interacts with PARP1. The enzymatic function of IMPDH2, which consumes NAD+, modulates PARP1 activity, thus mediating a pondered DNA damage response. However, forcing the nuclear localization of exogenous IMPDH2 provokes a dramatic NAD+ depletion that results in PARP1 cleavage and consequent cytoplasmic translocation, which mediates apoptosis. Our study identifies a moonlighting role for IMPDH2 in the control of nuclear ATP and NAD+ level, which fine-tune the activation of PARP1 and regulates the DNA damage response.
HostingRepository	PRIDE
AnnounceDate	2024-11-28
AnnouncementXML	Submission_2024-11-28_05:35:58.052.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eduard Sabidó
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-04 01:35:05	ID requested
⏵ 1	2024-11-28 05:35:58	announced

10.1038/S41467-024-53877-Z;

submitter keyword: proteomics,PARP1, IMPDH2, DNA damage

Eduard Sabidó
contact affiliation	Centre for Genomic Regulation
contact email	eduard.sabido@crg.cat
lab head
Eduard Sabidó
contact affiliation	Centre de Regulació Genòmica
contact email	eduard.sabido@crg.cat
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/2024/11/PXD043522

PRIDE project URI

• PRIDE
  1. PXD043522
     1. Label: PRIDE project
     2. Name: Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity