PXD060648

PXD060648 is an original dataset announced via ProteomeXchange.

Title	Integrator loss leads to dsRNA formation that triggers the Integrated Stress Response
Description	Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT-depletion causes upregulation of short genes such as the ISR transcription factor ATF3. Further, immature RNAPII that escapes into genes upon INT-depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by Protein Kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT-deficiency.
HostingRepository	PRIDE
AnnounceDate	2026-01-08
AnnouncementXML	Submission_2026-01-08_09:47:36.136.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kyle Swovick
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-10 11:53:15	ID requested
⏵ 1	2026-01-08 09:47:36	announced

Dataset with its publication pending

submitter keyword: RNA polyermase II, integrated stress response,Integrator, intron

Eric Wagner
contact affiliation	University of Rochester School of Medicine and Dentristry, Department of Biochemistry and Biophysics
contact email	Eric_Wagner@URMC.Rochester.edu
lab head
Kyle Swovick
contact affiliation	University of Rochester Medical Center Mass Spectrometry Shared Resource Laboratory
contact email	kswovick@ur.rochester.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060648
     1. Label: PRIDE project
     2. Name: Integrator loss leads to dsRNA formation that triggers the Integrated Stress Response