PXD047837-2

PXD047837 is an original dataset announced via ProteomeXchange.

Title	ATM Inhibition Exploits Checkpoint Defects and ATM-Dependent Double Strand Break Repair in TP53-Mutant Glioblastoma
Description	Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a novel method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). This approach revealed enhanced MMEJ and HR in glioblastoma (GBM) xenograft models with acquired temozolomide (TMZ) resistance. Knockdown of proteins in either pathway enhanced killing by TMZ, and a targeted screen identified pharmacological-grade dual HR/MMEJ inhibitors, including AZD1390, an ATM kinase inhibitor. AZD1390 suppressed DSB end resection, blocked phosphorylation of end protection proteins in response to DNA damage, and potentiated TMZ in treatment-naïve and treatment-resistant models. TP53-mutant GBMs were most susceptible to AZD1390 in combination with DNA-damaging agents due to elevated ATM-dependent HR/MMEJ, preferential activation of these pathways in response to DNA damage, and a defective G2/M checkpoint, which caused these GBMs to enter mitosis despite unrepaired DNA damage, leading to cell death via apoptosis. This report establishes ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:32:41.355.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gary Bradshaw
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-14 11:57:38	ID requested
1	2024-03-08 10:47:38	announced
⏵ 2	2024-10-22 06:32:41	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: DNA double strand break repair,TP53-Mutant Glioblastoma, ATM Inhibition

Zachary D. Nagel
contact affiliation	1. Harvard T.H. Chan School of Public Health, Boston, MA 02115
contact email	znagel@hsph.harvard.edu
lab head
Gary Bradshaw
contact affiliation	Harvard Medical School
contact email	Gary_bradshaw@hms.harvard.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/2024/03/PXD047837

PRIDE project URI

• PRIDE
  1. PXD047837
     1. Label: PRIDE project
     2. Name: ATM Inhibition Exploits Checkpoint Defects and ATM-Dependent Double Strand Break Repair in TP53-Mutant Glioblastoma