Journal Article

Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair

Takahashi, Yoshito, Tateishi, Satoshi, Ogi, Tomoo, Ito, Kosei, Lehmann, Alan R, Kudo, Takashi, Yamashita, Shunichi, Slor, Hanoch, Mitsutake, Norisato, Ono, Shinji, Kinoshita, Akira, Ohyama, Kaname, Mishima, Hiroyuki, Masuyama, Ritsuko, Nakazawa, Yuka, Sasaki, Kensaku, Shimada, Mayuko, Nardo, Tiziana, Matsuse, Michiko, Stefanini, Miria, Utani, Atsushi, Takenaka, Katsuya, Yoshiura, Koh-ichiro, Nomura, Masayo

2012

Overview

Tomoo Ogi and colleagues report mutations of UVSSA causing a third complementation group of the UV-sensitive syndrome. UVSSA deficiency results in defective transcription-coupled nucleotide-excision repair and failure to resolve stalled RNA polymerase IIo at DNA damage sites. UV-sensitive syndrome (UV S S) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma 1 , 2 , 3 , 4 . 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) 2 , 4 , 5 , which removes DNA damage in actively transcribed genes 6 . 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) 7 , 8 . The remaining four individuals with UV S S, one of whom is described for the first time here, formed a separate UV S S-A complementation group 1 , 9 , 10 ; however, the responsible gene was unknown. Using exome sequencing 11 , 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/208/514 / Agriculture / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carrier Proteins - genetics / Causes of / Cockayne Syndrome - genetics / Complex syndromes / Deoxyribonucleic acid / DNA / DNA Damage - genetics / DNA Damage - radiation effects / DNA Helicases - chemistry / DNA Helicases - genetics / DNA Repair - genetics / DNA Repair - radiation effects / DNA Repair Enzymes - chemistry / DNA Repair Enzymes - genetics / Exome - genetics / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genes / Genetic aspects / Genetic disorders / Genetic research / Genetic transcription / Genetics of eukaryotes. Biological and molecular evolution / Health aspects / Human Genetics / Humans / Kinases / letter / Medical genetics / Medical research / Medical sciences / Molecular and cellular biology / Molecular genetics / Mutation / Mutation - genetics / Poly-ADP-Ribose Binding Proteins / Proteins / RNA Polymerase II - genetics / RNA Polymerase II - metabolism / RNA polymerases / Skin diseases / Transcription Factors - chemistry / Transcription Factors - genetics / Transcription, Genetic / Transcription. Transcription factor. Splicing. Rna processing / Ultraviolet Rays