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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Primary accessions



  1. 1.

    , , & Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response. Mol. Cell 46, 625–635 (2012).

  2. 2.

    et al. DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. Nat. Struct. Mol. Biol. 19, 1093–1100 (2012).

  3. 3.

    et al. DVC1 (C1orf124) is a DNA damage–targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. Nat. Struct. Mol. Biol. 19, 1084–1092 (2012).

  4. 4.

    et al. Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance. Nucleic Acids Res. 40, 10795–10808 (2012).

  5. 5.

    et al. Regulation of error-prone translesion synthesis by Spartan/C1orf124. Nucleic Acids Res. 41, 1661–1668 (2013).

  6. 6.

    , & Spartan/C1orf124 is important to prevent UV-induced mutagenesis. Cell Cycle 11, 3395–3402 (2012).

  7. 7.

    , , , & Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis. J. Biol. Chem. 287, 34225–34233 (2012).

  8. 8.

    & Progeria syndromes and ageing: what is the connection? Nat. Rev. Mol. Cell Biol. 11, 567–578 (2010).

  9. 9.

    & Architecture of inherited susceptibility to common cancer. Nat. Rev. Cancer 10, 353–361 (2010).

  10. 10.

    Genetic syndromes in man with potential relevance to the pathobiology of aging. Birth Defects Orig. Artic. Ser. 14, 5–39 (1978).

  11. 11.

    , & Molecular bases of progeroid syndromes. Hum. Mol. Genet. 15, R151–R161 (2006).

  12. 12.

    et al. Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am. J. Hum. Genet. 88, 650–656 (2011).

  13. 13.

    et al. LMNA mutations in atypical Werner's syndrome. Lancet 362, 440–445 (2003).

  14. 14.

    & Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome. Gerontology 60, 239–246 (2014).

  15. 15.

    et al. Atypical progeroid syndrome: an unknown helicase gene defect? Am. J. Med. Genet. A. 116A, 295–299 (2003).

  16. 16.

    , & Role of p97/VCP (Cdc48) in genome stability. Front. Genet. 4, 60 (2013).

  17. 17.

    et al. Ki-67 expression as a prognostic marker in patients with hepatocellular carcinoma. J. Gastroenterol. Hepatol. 13, 273–279 (1998).

  18. 18.

    , , & Molecular markers for cancer prognosis and treatment: have we struck gold? Cancer Lett. 327, 142–152 (2012).

  19. 19.

    et al. Variegated translocation mosaicism in human skin fibroblast cultures. Cytogenet. Cell Genet. 15, 282–298 (1975).

  20. 20.

    et al. Zebrafish mRNA sequencing deciphers novelties in transcriptome dynamics during maternal to zygotic transition. Genome Res. 21, 1328–1338 (2011).

  21. 21.

    & The Werner syndrome gene: the molecular basis of RecQ helicase–deficiency diseases. Trends Genet. 16, 213–220 (2000).

  22. 22.

    et al. Mutation at the polymerase active site of mouse DNA polymerase δ increases genomic instability and accelerates tumorigenesis. Mol. Cell. Biol. 27, 7669–7682 (2007).

  23. 23.

    & Maintaining genome stability at the replication fork. Nat. Rev. Mol. Cell Biol. 11, 208–219 (2010).

  24. 24.

    & Causes and consequences of replication stress. Nat. Cell Biol. 16, 2–9 (2014).

  25. 25.

    et al. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343, 88–91 (2014).

  26. 26.

    et al. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat. Cell Biol. 13, 243–253 (2011).

  27. 27.

    , , & The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest. Cell Cycle 7, 796–807 (2008).

  28. 28.

    , & Role for BLM in replication-fork restart and suppression of origin firing after replicative stress. Nat. Struct. Mol. Biol. 14, 677–679 (2007).

  29. 29.

    & The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat. Rev. Cancer 7, 861–869 (2007).

  30. 30.

    Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011).

  31. 31.

    & The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology. J. Gastroenterol. 44 (suppl. 19), 96–101 (2009).

  32. 32.

    , , & Essential function of Chk1 can be uncoupled from DNA damage checkpoint and replication control. Proc. Natl. Acad. Sci. USA 105, 20752–20757 (2008).

  33. 33.

    et al. Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42. Am. J. Hum. Genet. 88, 127–137 (2011).

  34. 34.

    & Generating linkage mapping files from Affymetrix SNP chip data. Bioinformatics 25, 1961–1962 (2009).

  35. 35.

    , , & Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

  36. 36.

    et al. Estimation of the inbreeding coefficient through use of genomic data. Am. J. Hum. Genet. 73, 516–523 (2003).

  37. 37.

    et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).

  38. 38.

    et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

  39. 39.

    , & ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

  40. 40.

    et al. Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327, 78–81 (2010).

  41. 41.

    & HapCUT: an efficient and accurate algorithm for the haplotype assembly problem. Bioinformatics 24, i153–i159 (2008).

  42. 42.

    et al. Coronary artery disease in a Werner syndrome–like form of progeria characterized by low levels of progerin, a splice variant of lamin A. Am. J. Med. Genet. A. 155A, 3002–3006 (2011).

  43. 43.

    et al. Ethnic-specific WRN mutations in South Asian Werner syndrome patients: potential founder effect in patients with Indian or Pakistani ancestry. Mol. Genet. Genomic Med. 1, 7–14 (2013).

  44. 44.

    & Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells. J. Cell Biol. 140, 1285–1295 (1998).

  45. 45.

    , , & ATR and ATRIP: partners in checkpoint signaling. Science 294, 1713–1716 (2001).

  46. 46.

    et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat. Genet. 44, 910–915 (2012).

Download references


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.

Author information

Author notes

    • Davor Lessel
    • , Bruno Vaz
    • , Swagata Halder
    • , Paul J Lockhart
    •  & Ivana Marinovic-Terzic

    These authors contributed equally to this work.


  1. Institute of Human Genetics, University of Ulm, Ulm, Germany.

    • Davor Lessel
    • , Gotthold Barbi
    • , Simon von Ameln
    • , Josef Högel
    •  & Christian Kubisch
  2. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Davor Lessel
    •  & Christian Kubisch
  3. Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.

    • Bruno Vaz
    • , Swagata Halder
    • , Judith Oehler
    •  & Kristijan Ramadan
  4. Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.

    • Swagata Halder
    • , Judith Oehler
    • , Regina Fertig
    •  & Kristijan Ramadan
  5. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

    • Paul J Lockhart
    • , Joe C H Sim
    • , Kate Pope
    • , Martin B Delatycki
    •  & David J Amor
  6. Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

    • Paul J Lockhart
    • , Richard J Leventer
    • , Martin B Delatycki
    •  & David J Amor
  7. Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.

    • Ivana Marinovic-Terzic
    • , Marina Degoricija
    •  & Janos Terzic
  8. Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt (Main), Germany.

    • Jaime Lopez-Mosqueda
    •  & Ivan Dikic
  9. Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt (Main), Germany.

    • Jaime Lopez-Mosqueda
    •  & Ivan Dikic
  10. Department of Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany.

    • Melanie Philipp
  11. Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.

    • Katherine R Smith
    • , Amsha Nahid
    •  & Melanie Bahlo
  12. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

    • Katherine R Smith
  13. Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Tenerife, Spain.

    • Elisa Cabrera
    •  & Raimundo Freire
  14. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

    • Fiona Norris
  15. Neuroscience Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

    • Richard J Leventer
  16. Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.

    • Richard J Leventer
  17. Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.

    • Martin B Delatycki
  18. Leibniz Institute for Age Research, Fritz Lippmann Institute, Jena, Germany.

    • Martin D Burkhalter
  19. Institute of Genetics, University of Cologne, Cologne, Germany.

    • Kay Hofmann
  20. Cologne Center for Genomics, University of Cologne, Cologne, Germany.

    • Holger Thiele
    • , Janine Altmüller
    • , Gudrun Nürnberg
    •  & Peter Nürnberg
  21. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  22. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  23. Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.

    • Melanie Bahlo
  24. Department of Pathology, University of Washington, Seattle, Washington, USA.

    • George M Martin
    •  & Junko Oshima
  25. Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, the Netherlands.

    • Cora M Aalfs


  1. Search for Davor Lessel in:

  2. Search for Bruno Vaz in:

  3. Search for Swagata Halder in:

  4. Search for Paul J Lockhart in:

  5. Search for Ivana Marinovic-Terzic in:

  6. Search for Jaime Lopez-Mosqueda in:

  7. Search for Melanie Philipp in:

  8. Search for Joe C H Sim in:

  9. Search for Katherine R Smith in:

  10. Search for Judith Oehler in:

  11. Search for Elisa Cabrera in:

  12. Search for Raimundo Freire in:

  13. Search for Kate Pope in:

  14. Search for Amsha Nahid in:

  15. Search for Fiona Norris in:

  16. Search for Richard J Leventer in:

  17. Search for Martin B Delatycki in:

  18. Search for Gotthold Barbi in:

  19. Search for Simon von Ameln in:

  20. Search for Josef Högel in:

  21. Search for Marina Degoricija in:

  22. Search for Regina Fertig in:

  23. Search for Martin D Burkhalter in:

  24. Search for Kay Hofmann in:

  25. Search for Holger Thiele in:

  26. Search for Janine Altmüller in:

  27. Search for Gudrun Nürnberg in:

  28. Search for Peter Nürnberg in:

  29. Search for Melanie Bahlo in:

  30. Search for George M Martin in:

  31. Search for Cora M Aalfs in:

  32. Search for Junko Oshima in:

  33. Search for Janos Terzic in:

  34. Search for David J Amor in:

  35. Search for Ivan Dikic in:

  36. Search for Kristijan Ramadan in:

  37. Search for Christian Kubisch in:


D.L., B.V., S.H., P.J.L., I.M.-T., J.L.-M., M.P., J.C.H.S., K.R.S., J. Oehler, K.P., A.N., F.N., R.J.L., M.B.D., G.B., S.v.A., J.H., M.D., R. Fertig, M.D.B., K.H., H.T., J.A., G.N., P.N. and M.B. performed the experiments and did data analysis. E.C., R. Freire, J. Oshima, G.M.M. and C.M.A. contributed materials and reagents used in the study. D.L., K.R. and C.K. wrote the manuscript. J.T., D.J.A., I.D., K.R. and C.K. led and coordinated the entire project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Janos Terzic or David J Amor or Ivan Dikic or Kristijan Ramadan or Christian Kubisch.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15 and Supplementary Tables 1–5

About this article

Publication history






Further reading