Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1)1,2,3,4,5,6,7 in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis1,2,3,4,5,6,7. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.
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NCBI Reference Sequence
We are thankful to the family members for participation, G. Gillies for assistance with patient samples, J. Schäfer for zebrafish care and Z. Garajova for technical assistance. We thank A. Ray Chaudhuri for initial help with the DNA fiber assay. We thank F. Böhm, Y. Böge and A. Weber from the University of Zurich and L. Campo and K. Myers from the University of Oxford for providing healthy and HCC human liver biopsies and performing histological and immunohistochemical staining. The zebrafish γ-H2AX antibody was a kind gift of J. Amatruda (University of Texas Southwestern). This work was supported by grants from Deutsche Forschungsgemeinschaft, the Cluster of Excellence 'Macromolecular Complexes' of Goethe University Frankfurt (EXC115), the Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz program Ubiquitin Networks of the State of Hesse, Germany and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/European Research Council grant agreement number 250241-LineUb to I.D., the European Commission (Marie Curie Reintegration Grant 268333 to M.P.), the Deutsche Stiftung für Herzforschung (M.P.), the Medical Research Council (MC_PC_12001/1) and the Swiss National Science Foundation (31003A_141197) to K.R., grants from the US National Institutes of Health (NIH) National Cancer Institute (R24CA78088 and R24AG042328) to G.M.M., the NIH National Institute on Aging (R21AG033313) to J. Oshima, the Ellison Medical Foundation to J. Oshima, the German Research Foundation (DFG) in the framework of the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases to C.K., an EMBO long-term fellowship to J.L.-M., a grant from the Croatian Ministry of Science, Education and Sport (216-0000000-3348) and a City of Split grant to J.T. and I.D. K.R.S. is supported by a PhD scholarship funded by the Pratt Foundation. M.B. is supported by an Australian Research Council Future Fellowship (FT100100764). P.J.L. is supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship (APP1032364). This work was made possible through Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme.
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Supplementary Figures 1–15 and Supplementary Tables 1–5
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Nature Reviews Molecular Cell Biology (2017)