XPC and global genome nucleotide excision repair are essential for telomere stability after UVC-induced DNA damage in human cells.

Telomeric sequences are hotspots for ultraviolet light (UV) induced cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone photoproducts (6-4 PP), due to pyrimidine runs on both the TTAGGG and CCCTAA containing strands. Photoproducts are repaired by global genome nucleotide excision repair (GG-NER) or by transcription-coupled (TC-NER) in regions of active transcription. Since telomeres are transcribed into long telomeric repeat-containing RNA (TERRA) molecules, here we tested roles for both TC-NER and GG-NER in telomere stability following UVC irradiation. XPC-deficient cells, incapable of GG-NER, failed to exhibit significant reductions in 6-4 PPs and CPDs at telomeres during recovery times, indicating that TC-NER cannot compensate for detectable photoproduct removal at telomeres when GG-NER is absent. TERRA analysis confirmed active telomere transcription in these cell lines. Loss of total NER or specifically GG-NER in XPA-deficient or XPC-deficient cells, respectively, increased telomere losses and telomere fragility following UV irradiation. These data provide direct evidence that NER is required to prevent UV damage-induced telomere aberrations and that transcription at telomeres is likely insufficient to drive substantial TC-NER-mediated photoproduct removal.