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

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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Figure 1: Identification of truncation mutations in the UVSSA gene in subjects with UVSS-A.
Figure 2: RNA synthesis recovery after UV irradiation requires UVSSA gene expression.
Figure 3: The N-terminal VHS domain of the UVSSA protein is essential for RRS activity and TFIIH interaction.
Figure 4: The UVSSA VHS domain is essential for the processing of RNA Pol IIo.

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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.).

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Authors and Affiliations

Authors

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.

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Correspondence to Tomoo Ogi.

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Supplementary Tables 1–4, Supplementary Figures 1–15 and Supplementary Note (PDF 4474 kb)

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Nakazawa, Y., Sasaki, K., Mitsutake, N. et al. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair. Nat Genet 44, 586–592 (2012). https://doi.org/10.1038/ng.2229

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