PXD008299

PXD008299 is an original dataset announced via ProteomeXchange.

Title	UBQLN4, a regulator of protein dynamics at sites of DNA damage, is lost in a new genome instability syndrome and elevated in aggressive tumors
Description	The ubiquitin-proteasome system (UPS) plays a crucial role in cellular homeostasis, but the mechanistic aspects of its involvement in the DNA damage response (DDR) remain largely elusive. Here, we identify a homozygous truncation mutation in the UBQLN4 gene in families with highly pleiotropic autosomal recessive syndrome, with clinical and cellular characteristics reminiscent of DNA repair disorders. UBQLN4 loss leads to hypersensitivity to genotoxic stress and delayed repair of DNA double-strand breaks (DSBs). By dissecting the molecular mechanism of action, we find an ATM-dependent phosphorylation site on UBQLN4 (Ser-318), which is required for the cellular protection against DNA damage and proper DSB repair. UBQLN4 is a known proteasomal shuttle factor for ubiquitinated proteins and we demonstrate that loss of UBQLN4 leads to the accumulation and retention of MRE11 and RPA70 at DSB sites. Concomitantly, we find that UBQLN4 loss of function is associated with a relative increase in homologous recombination-mediated DSB repair and a reduced usage of non-homologous end joining. In contrast, UBQLN4 overexpression represses HRR usage. We show that this UBQLN4-driven preference for NHEJ-mediated DSB repair is conserved in C. elegans. Moreover, a detailed analysis of human neuroblastoma and melanoma cancer samples reveals that UBQLN4 is overexpressed in aggressive tumors. In line with a HRR defect, we observe that tumor cells overexpressing UBQLN4 display an actionable PARP1 inhibitor sensitivity. Thus, we identify a novel DDR component, which may be a promising target for PARP1 inhibition in aggressive cancer.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:06:42.231.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tamar Geiger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-11-27 01:52:31	ID requested
1	2020-06-02 06:13:38	announced
⏵ 2	2024-10-22 05:06:46	announced	2024-10-22: Updated project metadata.

10.1016/j.cell.2018.11.024;

Jachimowicz RD, Beleggia F, Isensee J, Velpula BB, Goergens J, Bustos MA, Doll MA, Shenoy A, Checa-Rodriguez C, Wiederstein JL, Baranes-Bachar K, Bartenhagen C, Hertwig F, Teper N, Nishi T, Schmitt A, Distelmaier F, L, ü, decke HJ, Albrecht B, Kr, ü, ger M, Schumacher B, Geiger T, Hoon DSB, Huertas P, Fischer M, Hucho T, Peifer M, Ziv Y, Reinhardt HC, Wieczorek D, Shiloh Y, UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell, 176(3):505-519.e22(2019) [pubmed]

curator keyword: Biomedical

submitter keyword: DNA damage, LC-MS, Proteomics,UBQLN4

Tamar Geiger
contact affiliation	Department of human molecular genetics and biochemistry, Sackler faculty of medicine, Tel Aviv University, Israel.
contact email	geiger@tauex.tau.ac.il
lab head
Tamar Geiger
contact affiliation	Weizmann Institute of Science
contact email	geiger@tauex.tau.ac.il
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/2020/06/PXD008299

PRIDE project URI

• PRIDE
  1. PXD008299
     1. Label: PRIDE project
     2. Name: UBQLN4, a regulator of protein dynamics at sites of DNA damage, is lost in a new genome instability syndrome and elevated in aggressive tumors