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Nakazawa_UVSSA_NG_2012_Figs.pdf (7.36 MB)

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

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posted on 2023-06-15, 13:56 authored by Yuka Nakazawa, Kensaku Sasaki, Norisato Mitsutake, Michiko Matsuse, Mayuko Shimada, Tiziana Nardo, Yoshito Takahashi, Kaname Ohyama Ohyama, Kosei Ito, Hiroyuki Mishima, Masayo Nomura, Akira Kinoshita, Shinji Ono, Katsuya Takenaka, Ritsuko Masuyama, Takashi Kudo, Hanoch Slor, Atsushi Utani, Satoshi Tateishi, Shunichi Yamashita, Miria Stefanini, Alan LehmannAlan Lehmann, Koh-ichiro Yoshiura, Tomoo Ogi
UV-sensitive syndrome (UVSS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma1, 2, 3, 4. Despite mild clinical features, cells from individuals with UVSS, 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 genes6. Three of the seven known UVSS 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 UVSS, one of whom is described for the first time here, formed a separate UVSS-A complementation group1, 9, 10; however, the responsible gene was unknown. Using exome sequencing11, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UVSS-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.

History

Publication status

  • Published

Journal

Nature Genetics

ISSN

1061-4036

Publisher

Nature Publishing Group

Issue

5

Volume

44

Page range

586-592

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2012-05-15

First Compliant Deposit (FCD) Date

2012-05-15

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