PXD011108

PXD011108 is an original dataset announced via ProteomeXchange.

Title	ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
Description	Mutations in the ATM tumor suppressor gene confer cellular hypersensitivity to various DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms towards such drugs, we performed genome-wide CRISPR-Cas9 loss-of-function screens in cells treated with the DNA topoisomerase I poison topotecan. Our ensuing characterizations of hits established that loss of terminal components of the non-homologous end joining (NHEJ) machinery or components of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. Our findings indicate that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib is due to delayed engagement of homologous recombination repair (HRR) at a subset of DNA-replication-fork associated single ended double-strand breaks (seDSBs), which allows non-homologous end joining (NHEJ) mediated repair, resulting in toxic chromosome fusions. Thus, restoration of legitimate repair in ATM-deficient cells – either by preventing the DNA ligation step of NHEJ or by enhancing HRR engagement by deregulating the BRCA1-A complex – markedly suppresses this toxicity. We conclude that the crucial role for ATM at seDSBs is to prevent toxic LIG4-mediated NHEJ at damaged replication forks. Furthermore, our observation that suppressor mutations in ATM-mutant backgrounds are fundamentally different to those that operate in BRCA1-mutant scenarios suggests new opportunities for patient stratification in the clinic, as well as additional therapeutic vulnerabilities that might be exploited in drug-resistant cancers.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:48:50.248.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Petra Beli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-09-17 02:59:49	ID requested
1	2019-11-12 14:23:29	announced
⏵ 2	2024-10-22 04:48:58	announced	2024-10-22: Updated project metadata.

10.1038/s41467-018-07729-2;

Balmus G, Pilger D, Coates J, Demir M, Sczaniecka-Clift M, Barros AC, Woods M, Fu B, Yang F, Chen E, Ostermaier M, Stankovic T, Ponstingl H, Herzog M, Yusa K, Martinez FM, Durant ST, Galanty Y, Beli P, Adams DJ, Bradley A, Metzakopian E, Forment JV, Jackson SP, ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks. Nat Commun, 10(1):87(2019) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: ATM, DNA damage response

Petra Beli
contact affiliation	Institute of Molecular Biology (IMB), Mainz, Germany
contact email	p.beli@imb-mainz.de
lab head
Petra Beli
contact affiliation	Institute of Molecular Biology (IMB), Mainz, Germany
contact email	p.beli@imb-mainz.de
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/2019/11/PXD011108

PRIDE project URI

• PRIDE
  1. PXD011108
     1. Label: PRIDE project
     2. Name: ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks