Abstract

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.

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Acknowledgements

We are grateful to P. Hanawalt and G. Spivak for their helpful comments on the manuscript. We are grateful to C. Hayashida, M. Kawamichi and H. Fawcett for technical assistance. This work was supported by Special Coordination Funds for Promoting Science and Technology from the Japan Science and Technology Agency (JST) (to Y.N., K.O., K.I., R.M. and T.O.), a grant-in-aid for Scientific Research KAKENHI (22710056) from the Japanese Society for the Promotion of Science, a science research grant from the Inamori Foundation, a cancer research grant from The Sagawa Foundation for Promotion of Cancer Research, a medical research grant from Mochida Memorial Funds for Medical and Pharmaceutical Research, a medical research grant from the Daiichi-Sankyo Foundation of Life Science, a medical research grant from the Takeda Science Foundation, a grant-in-aid for Seeds Innovation (Type-A) from JST (to T.O.), a Global Centers of Excellence (COE) Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y.N., K.S., N.M., M.M., M. Shimada, S.Y., K.Y. and T.O.), grants from the Ministry of Health, Labour and Welfare (to K.Y.), the Associazione Italiana per la Ricerca sul Cancro (to M. Stefanini), a Medical Research Council (MRC) programme grant and an EC-RTN and integrated project (to A.R.L.).

Author information

Author notes

    • Yuka Nakazawa
    • , Kensaku Sasaki
    •  & Norisato Mitsutake

    These authors contributed equally to this work.

Affiliations

  1. Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (NRGIC), Nagasaki, Japan.

    • Yuka Nakazawa
    • , Norisato Mitsutake
    • , Michiko Matsuse
    • , Mayuko Shimada
    • , Kaname Ohyama
    • , Kosei Ito
    • , Akira Kinoshita
    •  & Tomoo Ogi
  2. Department of Molecular Medicine, Atomic Bomb Disease Institute, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

    • Yuka Nakazawa
    • , Mayuko Shimada
    •  & Tomoo Ogi
  3. Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

    • Yuka Nakazawa
    • , Norisato Mitsutake
    • , Michiko Matsuse
    • , Mayuko Shimada
    • , Shunichi Yamashita
    •  & Tomoo Ogi
  4. Department of Human Genetics, Atomic Bomb Disease Institute, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

    • Kensaku Sasaki
    • , Hiroyuki Mishima
    • , Masayo Nomura
    • , Akira Kinoshita
    • , Shinji Ono
    •  & Koh-ichiro Yoshiura
  5. Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy.

    • Tiziana Nardo
    •  & Miria Stefanini
  6. Innovative Beauty Science Laboratory, Kanebo Cosmetics Inc., Odawara, Japan.

    • Yoshito Takahashi
  7. Department of Environmental and Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

    • Kaname Ohyama
  8. Department of Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

    • Kosei Ito
    •  & Ritsuko Masuyama
  9. Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

    • Katsuya Takenaka
  10. Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

    • Takashi Kudo
  11. Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Hanoch Slor
  12. Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

    • Atsushi Utani
  13. Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.

    • Satoshi Tateishi
  14. Fukushima Medical University, Fukushima, Japan.

    • Shunichi Yamashita
  15. Genome Damage and Stability Centre, University of Sussex, Brighton, UK.

    • Alan R Lehmann

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Contributions

N.M. and T.O. designed the study and experiments. Y.N., N.M., M.M., M. Shimada, T.N., K.O., K.I., K.T., R.M. and T.O. performed molecular and cell biology experiments. Y.N., K.S., M. Shimada, Y.T., M.N., A.K., S.O., K.Y. and T.O. performed genetic experiments. K.S., M. Shimada, Y.T., H.M., M.N., A.K., S.O., K.Y. and T.O. analyzed the genetic data. Y.T., H.S., A.U., S.T., M. Stefanini and A.R.L. contributed Cockayne syndrome and UVSS subject materials. N.M., Y.T., T.K., A.U., S.Y., M. Stefanini, A.R.L., K.Y. and T.O. coordinated the study. N.M., M. Stefanini, A.R.L. and T.O. wrote the manuscript. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tomoo Ogi.

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DOI

https://doi.org/10.1038/ng.2229

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