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 C. Smyrk; Yusuke Kojima; Yuka Machida; Annyoceli Santiago; Jan M. Van Deursen; Scott H. Kaufmann; Yuichi J. Machida

doi:10.1093/nar/gkx107

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 C. Smyrk, Yusuke Kojima, Yuka Machida, Annyoceli Santiago, Jan M. Van Deursen, Scott H. Kaufmann, Yuichi J. Machida

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45 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	4564-4576
Number of pages	13
Journal	Nucleic acids research
Volume	45
Issue number	8
DOIs	https://doi.org/10.1093/nar/gkx107
State	Published - May 5 2017

ASJC Scopus subject areas

Genetics

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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. M., Kaufmann, S. H., & Machida, Y. J. (2017). Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis. Nucleic acids research, 45(8), 4564-4576. https://doi.org/10.1093/nar/gkx107

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title = "Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis",

abstract = "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.",

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

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doi = "10.1093/nar/gkx107",

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T1 - Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis

AU - Maskey, Reeja S.

AU - Flatten, Karen S.

AU - Sieben, Cynthia J.

AU - Peterson, Kevin L.

AU - Baker, Darren J.

AU - Nam, Hyun Ja

AU - Kim, Myoung Shin

AU - Smyrk, Thomas C.

AU - Kojima, Yusuke

AU - Machida, Yuka

AU - Santiago, Annyoceli

AU - Van Deursen, Jan M.

AU - Kaufmann, Scott H.

AU - Machida, Yuichi J.

PY - 2017/5/5

Y1 - 2017/5/5

N2 - 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.

AB - 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.

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JO - Nucleic acids research

JF - Nucleic acids research

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Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis

Abstract

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