PXD033520

PXD033520 is an original dataset announced via ProteomeXchange.

Title	A disease-associated XPA allele interferes with TFIIH binding and primarily affects the transcription-coupled sub-pathway of nucleotide excision repair
Description	XPA is a central scaffold protein in nucleotide excision repair (NER) that interacts with and coordinates the assembly of repair complexes. Inactivating mutations in XPA causes Xeroderma Pigmentosum (XP), which is characterized by extreme UV sensitivity and a highly elevated skin cancer risk. Here, we describe two Dutch siblings in their late forties carrying a homozygous H244R substitution in the C-terminus of XPA with a mild manifestation of XP without skin cancer, but with neurological features including cerebellar ataxia. We show that the mutant XPA protein shows a severely weakened interaction with the TFIIH complex leading to its inefficient association with NER complexes and an inability to support the efficient association of the ERCC1-XPF endonuclease with repair complexes. Despite these defects, we find that patient-derived fibroblasts and reconstituted knockout cells carrying the H244R substitution show considerable levels of residual global genome repair (~40%), which is in intrinsic property of the mutated protein as revealed by in vitro experiments. In contrast, patient fibroblasts and engineered cells only expressing the mutant XPA protein were fully deficient in transcription-coupled repair. We report a new case of XPA deficiency that interferes with TFIIH binding and primarily affects the transcription-coupled sub-pathway of nucleotide excision repair, which is more closely associated with neurological features than to skin abnormalities.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:56:06.385.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Román González-Prieto
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-28 01:22:47	ID requested
1	2023-02-19 14:40:01	announced
⏵ 2	2023-11-14 08:56:06	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: Nucleotide Excision Repair

Xeroderma Pigmentosum

Alfred Vertegaal
contact affiliation	Cell and Chemical Biology LUMC The Netherlands
contact email	vertegaal@lumc.nl
lab head
Román González-Prieto
contact affiliation	Andalusian Center for Regenerative Medicine and Cell Biology, CABIMER, University of Seville
contact email	roman.gonzalez@cabimer.es
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/2023/02/PXD033520

PRIDE project URI

• PRIDE
  1. PXD033520
     1. Label: PRIDE project
     2. Name: A disease-associated XPA allele interferes with TFIIH binding and primarily affects the transcription-coupled sub-pathway of nucleotide excision repair