Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis

Reeja S. Maskey, Karen S. Flatten, Cynthia J. Sieben, Kevin L. Peterson, Darren J Baker, Hyun Ja Nam, Myoung Shin Kim, Thomas Christopher Smyrk, Yusuke Kojima, Yuka Machida, Annyoceli Santiago, Jan Van Deursen, Scott H Kaufmann, Yuichi Machida

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30 Scopus citations


Germlinemutations inSPRTN cause Ruijs-Aalfs syndrome (RJALS), a disorder characterized by genome instability, progeria and early onset hepatocellular carcinoma. Spartan, the protein encoded by SPRTN, is a nuclear metalloprotease that is involved in the repair of DNA-protein crosslinks (DPCs). Although Sprtn hypomorphic mice recapitulate key progeroid phenotypes of RJALS, whether this model expressing low amounts of Spartan is prone to DPC repair defects and spontaneous tumors is unknown. Here, we showed that the livers of Sprtn hypomorphicmice accumulate DPCs containing Topoisomerase 1 covalently linked to DNA. Furthermore, these mice exhibited DNA damage, aneuploidy and spontaneous tumorigenesis in the liver. Collectively, these findings provide evidence that partial loss of Spartan impairs DPC repair and tumor suppression.

Original languageEnglish (US)
Pages (from-to)4564-4576
Number of pages13
JournalNucleic Acids Research
Issue number8
StatePublished - 2017


ASJC Scopus subject areas

  • Genetics

Cite this

Maskey, R. S., Flatten, K. S., Sieben, C. J., Peterson, K. L., Baker, D. J., Nam, H. J., Kim, M. S., Smyrk, T. C., Kojima, Y., Machida, Y., Santiago, A., Van Deursen, J., Kaufmann, S. H., & Machida, Y. (2017). Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis. Nucleic Acids Research, 45(8), 4564-4576.