title: Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis.
abstract: Germline mutations in SPRTN 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 hypomorphic mice 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.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Reeja S
authors.initials: RS
authors.lastname: Maskey
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Sieben
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Hyun-Ja
authors.initials: HJ
authors.lastname: Nam
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Myoung Shin
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Machida
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Annyoceli
authors.initials: A
authors.lastname: Santiago
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Yuichi J
authors.initials: YJ
authors.lastname: Machida
mesh_terms: D000782:Aneuploidy; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency* / Q000235:genetics; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D013577:Syndrome
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C000602442:Spartan protein, mouse; D004264:DNA Topoisomerases, Type I