title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA  polymerase IIo processing in transcription-coupled nucleotide-excision repair.
abstract: UV-sensitive syndrome (UV(S)S) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma. Despite mild clinical features, cells from individuals with UV(S)S, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes. Three of the seven known UV(S)S cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively). The remaining four individuals with UVSS , one of whom is described for the first time here, formed a separate UV(S)S-A complementation group; however, the responsible gene was unknown. Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UV(S)S-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders.
authors.affiliation: Nagasaki University Research Centre for Genomic Instability and Carcinogenesis, Nagasaki, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakazawa
authors.forename: Kensaku
authors.initials: K
authors.lastname: Sasaki
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsuse
authors.forename: Mayuko
authors.initials: M
authors.lastname: Shimada
authors.forename: Tiziana
authors.initials: T
authors.lastname: Nardo
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Kaname
authors.initials: K
authors.lastname: Ohyama
authors.forename: Kosei
authors.initials: K
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mishima
authors.forename: Masayo
authors.initials: M
authors.lastname: Nomura
authors.forename: Akira
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Shinji
authors.initials: S
authors.lastname: Ono
authors.forename: Katsuya
authors.initials: K
authors.lastname: Takenaka
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Masuyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Hanoch
authors.initials: H
authors.lastname: Slor
authors.forename: Atsushi
authors.initials: A
authors.lastname: Utani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tateishi
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.forename: Koh-ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ogi
mesh_terms: D002352:Carrier Proteins / 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; D059472:Exome / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D012319:RNA Polymerase II / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
chemical_list: D002352:Carrier Proteins; C095472:ERCC8 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; C573137:UVSSA protein, human; D012319:RNA Polymerase II; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes