Residual CSB activity explains mild UV-sensitive syndrome phenotype caused by CSB mutations.

Transcription-coupled nucleotide excision repair (TC-NER) safeguards transcription by repairing transcription-blocking lesions, which are highly cytotoxic if they remain unresolved. TC-NER is triggered when RNA polymerase II stalls at a transcription-blocking lesion and is recognized by CSB, followed by recruitment of the TC-NER factors CSA and UVSSA. The loss of any of these factors causes complete TC-NER deficiency. Pathogenic variants in CSB or CSA typically result in Cockayne syndrome, a disorder marked by neurodegeneration and severe premature aging, highlighting the importance of TC-NER. By contrast, pathogenic variants in UVSSA cause the much milder UV-sensitive syndrome, which is limited to cutaneous symptoms. Recently, this difference has been linked to the ability of UVSSA-deficient but not CSB- or CSA-deficient cells to clear stalled RNA polymerase II through proteasomal degradation, allowing alternative repair routes. Unexpectedly, patients with an early nonsense mutation in CSB (R77X), leading to undetectable protein levels, develop UV-sensitive syndrome rather than Cockayne syndrome. We examined this paradox and found that R77X cells can still degrade lesion-stalled RNA polymerase II, which is caused by residual but functional CSB expression in these cells. Together, our findings refine the model that defective RNA polymerase II processing is central to Cockayne syndrome pathogenesis and extend its relevance across TC-NER-related mutations.