PXD043645-1

PXD043645 is an original dataset announced via ProteomeXchange.

Title	PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects
Description	The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926A>C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5’-splice site (5’SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5’SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches.
HostingRepository	PRIDE
AnnounceDate	2024-03-01
AnnouncementXML	Submission_2024-03-01_04:34:01.957.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yanlong Ji
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-10 07:32:20	ID requested
⏵ 1	2024-03-01 04:34:02	announced

Dataset with its publication pending

submitter keyword: splicesome, PRPF8,human, LC-MS/MS

Henning Urlaub
contact affiliation	Bioanalytical Mass Spectrometry Group,Max-Planck-Institute for Multidisciplinary Sciences,Goettingen, Germany
contact email	henning.urlaub@mpinat.mpg.de
lab head
Yanlong Ji
contact affiliation	Max-Planck-Institute for Multidisciplinary Sciences
contact email	yanlong.ji@mpibpc.mpg.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/2024/03/PXD043645

PRIDE project URI

• PRIDE
  1. PXD043645
     1. Label: PRIDE project
     2. Name: PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects