PXD074100

PXD074100 is an original dataset announced via ProteomeXchange.

Title	Residual CSB activity explains UVSS caused by CSB mutations
Description	Transcription-Coupled Nucleotide Excision Repair (TC-NER) preserves transcriptional integrity by repairing transcription-blocking lesions (TBLs), which are highly cytotoxic if left unresolved. TC-NER is initiated when RNA Polymerase II (Pol II) stalls at a lesion and is recognized by CSB, followed by recruitment of CSA and UVSSA. Loss of any of these factors results in complete TC-NER deficiency. Inherited mutations in CSB and CSA typically cause Cockayne Syndrome (CS), characterized by neurodegeneration and severe premature aging, illustrating the biological importance of TC-NER. In contrast, mutations in UVSSA cause UV-sensitive syndrome (UVSS) with only mild cutaneous symptoms. These pronounced phenotypic differences have been attributed to the ability of UVSSA-deficient cells, but not CSB/A-deficient cells, to remove stalled Pol II form the lesion by proteasomal degradation, enabling alternative repair pathways. Strikingly, patients carrying an early nonsense mutation in CSB (R77X), resulting in undetectable CSB levels, develop UVSS rather than CS. To investigate this paradox, we studied patient-derived UVS1KO cells harboring the R77X mutation and found that, unlike CS-causing CSB mutations, these cells can still degrade lesion-stalled Pol II, although at reduced levels compared to TC-NER proficient cells. This is caused by residual CSB activity, as depletion of CSB in UVS1KO cells prevented removal of lesion-stalled Pol II by degradation and resulted in increased UV hypersensitivity. Consistent with this, we detected CSB in UVS1KO cells, although at a 100-fold lower level than in wild-type cells. Together, our findings confirm and refine the model that defective Pol II processing is central to CS pathogenesis and extend its relevance across TC-NER related mutations.
HostingRepository	PRIDE
AnnounceDate	2026-06-18
AnnouncementXML	Submission_2026-06-18_07:17:40.280.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jeroen Demmers
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-05 10:38:20	ID requested
⏵ 1	2026-06-18 07:17:40	announced

Dataset with its publication pending

submitter keyword: Transcription-Coupled Nucleotide Excision Repair (TC-NER), UVSS, CSB

Jeroen Demmers
contact affiliation	Proteomics Center | Erasmus MC
contact email	j.demmers@erasmusmc.nl
lab head
Jeroen Demmers
contact affiliation	Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands
contact email	j.demmers@erasmusmc.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD074100
     1. Label: PRIDE project
     2. Name: Residual CSB activity explains UVSS caused by CSB mutations