1. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair
- Author
-
Shunichi Yamashita, Alan R. Lehmann, Akira Kinoshita, Shinji Ono, Kaname Ohyama, Norisato Mitsutake, Michiko Matsuse, Katsuya Takenaka, Tomoo Ogi, Hiroyuki Mishima, Yuka Nakazawa, Kensaku Sasaki, Ritsuko Masuyama, Satoshi Tateishi, Yoshito Takahashi, Koh-ichiro Yoshiura, Takashi Kudo, Atsushi Utani, Miria Stefanini, Masayo Nomura, Kosei Ito, Tiziana Nardo, Mayuko Shimada, and Hanoch Slor
- Subjects
sequence analysis ,DNA Repair ,Transcription, Genetic ,ultraviolet stimulated scaffold protein a ,Cockayne syndrome ,suppressor of cytokine signaling ,chemistry.chemical_compound ,ultraviolet sensitive syndrome ,RNA polymerase ,Exome ,gene mutation ,Poly-ADP-Ribose Binding Proteins ,Genetics ,article ,unclassified drug ,priority journal ,RNA Polymerase II ,genodermatosis ,Transcription ,UV-sensitive syndrome ,Ultraviolet Rays ,DNA damage ,photosensitivity ,gene sequence ,Biology ,ubiquitination ,Genetic ,medicine ,Humans ,human ,Cockayne Syndrome ,Gene ,gene identification ,human cell ,DNA Helicases ,excision repair ,medicine.disease ,small interfering RNA ,Molecular biology ,DNA Repair Enzymes ,ERCC8 ,chemistry ,scaffold protein ,Mutation ,Carrier Proteins ,ERCC6 ,DNA Damage ,Transcription Factors - Abstract
UV-sensitive syndrome (UV SS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma. Despite mild clinical features, cells from individuals with UV SS, 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 SS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively). The remaining four individuals with UV SS, one of whom is described for the first time here, formed a separate UV SS-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 SS-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-NERg-deficient disorders., Nature Genetics, 44(5), pp.586-592; 2012
- Published
- 2012
- Full Text
- View/download PDF