PXD034887

PXD034887 is an original dataset announced via ProteomeXchange.

Title	Resistance to ATR Inhibitors Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2
Description	Over one million cases of gastric cancer are diagnosed each year and metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway creating therapeutic opportunities through synthetic lethal approaches. In particular, several small molecule inhibitors of Ataxia-Telangiectasia Mutated and Rad3-related protein kinase (ATR), a key regulator of the DNA Damage response, are now in clinical development as targeted agents for gastric cancer. Here, we sought to discover genetic determinants of response and resistance to ATRi in gastric cancer cells. We performed a large-scale CRISPR interference screen to discover determinants of resistance to ATRi in gastric cancer. Top hits were validated and further evaluated to define mechanisms of resistance. We identified components of the nonsense-mediated decay pathway and the UPF2 gene, in particular, as mediators of sensitivity to ATRi. We show loss of UPF2 causes resistance to ATRi through the abrogation of ATRi mediated cell cycle arrest and find evidence that UPF2 regulates R-loops. Our results uncover a novel role for NMD factors in R-loop formation and resistance to ATRi in gastric cancer cells, potentially through R-loop formation.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:48:28.929.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Minkyu Kim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-26 07:20:55	ID requested
1	2022-11-06 14:45:23	announced
⏵ 2	2023-11-14 07:48:32	announced	2023-11-14: Updated project metadata.

O'Leary PC, Chen H, Doruk YU, Williamson T, Polacco B, McNeal AS, Shenoy T, Kale N, Carnevale J, Stevenson E, Quigley DA, Chou J, Feng FY, Swaney DL, Krogan NJ, Kim M, Diolaiti ME, Ashworth A, Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2. Cancer Res, 82(21):3950-3961(2022) [pubmed]

submitter keyword: UPF2, Gastric cancer, AB, ph, NMD

Nevan Krogan
contact affiliation	Department of Cellular and Molecular Pharmacology, QUantitative Bioscience Institute, University of California, San Francisco
contact email	minkyu.kim@ucsf.edu
lab head
Minkyu Kim
contact affiliation	University of California San Francisco
contact email	minkyu.kim@ucsf.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034887
     1. Label: PRIDE project
     2. Name: Resistance to ATR Inhibitors Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2