title: UV-sensitive syndrome protein UVSSA recruits USP7 to  regulate transcription-coupled repair.
abstract: Transcription-coupled nucleotide-excision repair (TC-NER) is a subpathway of NER that efficiently removes the highly toxic RNA polymerase II blocking lesions in DNA. Defective TC-NER gives rise to the human disorders Cockayne syndrome and UV-sensitive syndrome (UV(S)S). NER initiating factors are known to be regulated by ubiquitination. Using a SILAC-based proteomic approach, we identified UVSSA (formerly known as KIAA1530) as part of a UV-induced ubiquitinated protein complex. Knockdown of UVSSA resulted in TC-NER deficiency. UVSSA was found to be the causative gene for UV(S)S, an unresolved NER deficiency disorder. The UVSSA protein interacts with elongating RNA polymerase II, localizes specifically to UV-induced lesions, resides in chromatin-associated TC-NER complexes and is implicated in stabilizing the TC-NER master organizing protein ERCC6 (also known as CSB) by delivering the deubiquitinating enzyme USP7 to TC-NER complexes. Together, these findings indicate that UVSSA-USP7–mediated stabilization of ERCC6 represents a critical regulatory mechanism of TC-NER in restoring gene expression.
authors.affiliation: Department of Genetics and Netherlands Proteomics Centre, Centre for Biomedical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Schwertman
authors.forename: Anna
authors.initials: A
authors.lastname: Lagarou
authors.forename: Dick H W
authors.initials: DH
authors.lastname: Dekkers
authors.forename: Anja
authors.initials: A
authors.lastname: Raams
authors.forename: Adriana C
authors.initials: AC
authors.lastname: van der Hoek
authors.forename: Charlie
authors.initials: C
authors.lastname: Laffeber
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Jeroen A A
authors.initials: JA
authors.lastname: Demmers
authors.forename: Maria
authors.initials: M
authors.lastname: Fousteri
authors.forename: Wim
authors.initials: W
authors.lastname: Vermeulen
authors.forename: Jurgen A
authors.initials: JA
authors.lastname: Marteijn
mesh_terms: D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D003057:Cockayne Syndrome / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004265:DNA Helicases / Q000737:chemistry* / Q000235:genetics; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D040901:Proteomics; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D014466:Ultraviolet Rays
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering; C573137:UVSSA protein, human; D025801:Ubiquitin; D012319:RNA Polymerase II; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes