PXD003529

PXD003529 is an original dataset announced via ProteomeXchange.

Title	Activation of the ATR kinase by the RPA-binding protein ETAA1
Description	The ATR kinase is a master regulator of cellular responses to DNA damage and replication stress that is activated by a complex mechanism involving its binding partner ATRIP, RPA-coated ssDNA, the 9-1-1 complex and TopBP1. Here, we discovered a new ATR activation mechanism in human cells, mediated by the uncharacterized protein ETAA1 (Ewing’s tumor-associated antigen 1). From a comprehensive proteomic survey of protein recruitment to DNA double-strand break-modified chromatin, we identified ETAA1 as a factor that accumulates at DNA damage sites via an RPA-binding motif, and which has an important role in promoting cell survival and preventing replication fork breakage after genotoxic insults. Mechanistically, we show that ETAA1 harbors a conserved domain that potently and directly stimulates ATR kinase activity independent of TopBP1 and 9-1-1, and which is essential for the function of ETAA1 in the DNA damage response. Consistently, ablation of ETAA1 shows profound synthetic lethality with TopBP1 knockdown, resulting from massive replication fork collapse and abrogation of ATR-dependent signaling. Finally, we show that ETAA1 levels in cancer cell lines inversely correlate with their dependency on TopBP1 for ATR activation, and that overexpression of ETAA1 partially restores ATR-dependent signaling after loss of TopBP1. Together, these findings establish a new mechanism of ATR activation in human cells that operates in parallel with, but independent of, the canonical TopBP1-mediated pathway.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:27:20.140.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Xenopus laevis (African clawed frog); NCBI TaxID: 8355; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2016-01-26 23:44:54	ID requested
1	2016-09-30 02:30:51	announced
2	2016-10-17 03:38:15	announced	Updated publication reference for PubMed record(s): 27723717.
⏵ 3	2024-10-22 04:27:28	announced	2024-10-22: Updated project metadata.

10.1038/ncb3422;

Haahr P, Hoffmann S, Tollenaere MA, Ho T, Toledo LI, Mann M, Bekker-Jensen S, R, ä, schle M, Mailand N, Activation of the ATR kinase by the RPA-binding protein ETAA1. Nat Cell Biol, 18(11):1196-1207(2016) [pubmed]

curator keyword: Biological

submitter keyword: DSB repair,CHROMASS, DNA damage response

Matthias Mann
contact affiliation	Department of Proteomics and Signal Transduction Max Planck Institute of Biochemistry
contact email	mmann@biochem.mpg.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD003529
     1. Label: PRIDE project
     2. Name: Activation of the ATR kinase by the RPA-binding protein ETAA1