Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair

UV-sensitive syndrome ((UVS)-S-S) is an autosomal recessive disorder characterized by photosensitivity and deficiency in transcription-coupled repair (TCR), a subpathway of nucleotide-excision repair that rapidly removes transcription-blocking DNA damage(1). Cockayne syndrome is a related disorder with defective TCR and consists of two complementation groups, Cockayne syndrome (CS)-A and CS-B, which are caused by mutations in ERCC8 (CSA) and ERCC6 (CSB), respectively(2). (UVS)-S-S comprises three groups, (UVS)-S-S/CS-A, (UVS)-S-S/CS-B and (UVS)-S-S-A, caused by mutations in ERCC8, ERCC6 and an unidentified gene, respectively(3-6). Here, we report the cloning of the gene mutated in (UVS)-S-S-A by microcell-mediated chromosome transfer. The predicted human gene UVSSA (formerly known as KIAA1530)(7) corrects defective TCR in (UVS)-S-S-A cells. We identify three nonsense and frameshift UVSSA mutations in individuals with (UVS)-S-S-A, indicating that UVSSA is the causative gene for this syndrome. The UVSSA protein forms a complex with USP7 (ref. 8), stabilizes ERCC6 and restores the hypophosphorylated form of RNA polymerase II after UV irradiation.