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Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair

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Abstract

UV-sensitive syndrome (UVSS) is an autosomal recessive disorder characterized by photosensitivity and deficiency in transcription-coupled repair (TCR), a subpathway of nucleotide-excision repair that rapidly removes transcription-blocking DNA damage1. Cockayne syndrome is a related disorder with defective TCR and consists of two complementation groups, Cockayne syndrome (CS)-A and CS-B, which are caused by mutations in ERCC8 (CSA) and ERCC6 (CSB), respectively2. UVSS comprises three groups, UVSS/CS-A, UVSS/CS-B and UVSS-A, caused by mutations in ERCC8, ERCC6 and an unidentified gene, respectively3,4,5,6. Here, we report the cloning of the gene mutated in UVSS-A by microcell-mediated chromosome transfer. The predicted human gene UVSSA (formerly known as KIAA1530)7 corrects defective TCR in UVSS-A cells. We identify three nonsense and frameshift UVSSA mutations in individuals with UVSS-A, indicating that UVSSA is the causative gene for this syndrome. The UVSSA protein forms a complex with USP7 (ref. 8), stabilizes ERCC6 and restores the hypophosphorylated form of RNA polymerase II after UV irradiation.

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Figure 1: CGH array analysis and identification of BAC clones encompassing mouse genomic DNA integrated in the 15A-7 and KAGB2-4 clones.
Figure 2: Mutations within the UVSSA gene in three subjects with UVsS-A.
Figure 3: Interaction of UVSSA with RNA Pol II, ERCC6, ERCC8 and USP7.
Figure 4: Degradation of ERCC6 in parental Kps3 cells, UVSSA-corrected Kps3 cells and normal cells transfected with USP7 siRNA after UV irradiation.

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Acknowledgements

We thank Y. Iwamoto and I. Kuraoka for their help in DNA sequencing and microcell-mediated chromosome transfer and M. Hoshi for her help in establishing Flp-In cells and performing immunoprecipitation. We also thank M. Yamaizumi (Kumamoto University Medical School) and N.G. Jaspers (Erasmus Medical Centre) for providing Kps3 cells and TA-24 cells, respectively. We thank G. Spivak for critical reading of the manuscript. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and by Health and Labor Sciences Research Grants for Research on Intractable Diseases (to K.T.). Part of this work was carried out under the Cooperative Research Project Program of the Institute of Development, Aging and Cancer (IDAC) at Tohoku University.

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Authors

Contributions

X.Z., K.H., M.S. and K.T. conceived the experiments. K.T. and H.T. established the cell lines. X.Z., K.H. and C.I. performed microcell-mediated chromosome transfer. A.U., K.H. and M.H. performed CGH array analysis. X.Z., M.S. and S.K. performed biochemical analysis. E.G.N. diagnosed Cockayne syndrome patients. K.T., X.Z., K.H., M.S., M.H., T.N. and A.Y. analyzed the data. K.T., X.Z., M.S. and K.H. wrote the manuscript.

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Correspondence to Kiyoji Tanaka.

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The authors declare no competing financial interests.

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Zhang, X., Horibata, K., Saijo, M. et al. Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. Nat Genet 44, 593–597 (2012). https://doi.org/10.1038/ng.2228

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