PXD053839

PXD053839 is an original dataset announced via ProteomeXchange.

Title	Trichothiodystrophy-causative pathogenic variants impair a cooperative action of TFIIH and DDX1 in R-loop processing
Description	The transcription factor IIH (TFIIH) is a key player in transcription and DNA repair by nucleotide excision repair. It is made of 10 subunits organized in core-TFIIH and CAK sub-complexes bridged by XPD. Pathogenic variants in the ERCC2/XPD gene give rise to xeroderma pigmentosum (XP) or trichothiodystrophy (TTD), two distinct clinical entities with opposite skin cancer proneness. Here, we show that TTD variants cause a partial dissociation of the CAK from the chromatin and from the core-TFIIH. Mass spectrometry analysis reveals that the chromatin-bound CAK, as a component of the entire TFIIH, participates in a protein assembly containing the RNA-binding proteins DDX1, SFPQ, NONO as well as RNA polymerase II (Pol II). Gene silencing experiments demonstrate that the protein assembly is required to process the DNA:RNA hybrids formed during Pol II extension and to protect the cell from transcriptional stress. TTD-specific variants in ERCC2/XPD result in TFIIH instability, altered interaction of the CAK with DDX1-SFPQ-NONO, and R-loop accumulation. Therefore, the limited amount of TFIIH that distinguishes TTD from XP gives rise to transcriptional stress and extensive gene expression deregulations, thus accounting for the wide spectrum of TTD clinical features.
HostingRepository	PRIDE
AnnounceDate	2025-08-08
AnnouncementXML	Submission_2025-08-08_00:45:44.705.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Enxhi Shaba
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	ultraflex

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-10 02:48:46	ID requested
⏵ 1	2025-08-08 00:45:45	announced

10.1093/NAR/GKAF745;

submitter keyword: XPD

TFIIH

DDX1

NONO

SFPQ

RNA polymerase II

R-loops

Nucleotide Excision Repair (NER)

trichothiodystrophy

xeroderma pigmentosum.

Prof. Luca
contact affiliation	Functional Proteomics Lab., Department of Life Sciences, University of Siena, 53100 Siena, Italy
contact email	luca.bini@unisi.it
lab head
Enxhi Shaba
contact affiliation	Functional Proteomics Lab, Life Sciences Department, University of Siena
contact email	enxhi.shaba@unisi.it
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/2025/08/PXD053839

PRIDE project URI

• PRIDE
  1. PXD053839
     1. Label: PRIDE project
     2. Name: Trichothiodystrophy-causative pathogenic variants impair a cooperative action of TFIIH and DDX1 in R-loop processing