title: Spartan deficiency causes genomic instability and progeroid phenotypes.
abstract: Spartan (also known as DVC1 and C1orf124) is a PCNA-interacting protein implicated in translesion synthesis, a DNA damage tolerance process that allows the DNA replication machinery to replicate past nucleotide lesions. However, the physiological relevance of Spartan has not been established. Here we report that Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Whereas complete loss of Spartan causes early embryonic lethality, hypomorphic mice with low amounts of Spartan are viable. These mice are growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Cre-mediated depletion of Spartan from conditional knockout mouse embryonic fibroblasts results in impaired lesion bypass, incomplete DNA replication, formation of micronuclei and chromatin bridges and eventually cell death. These data demonstrate that Spartan plays a key role in maintaining structural and numerical chromosome integrity and suggest a link between Spartan insufficiency and progeria.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Reeja S
authors.initials: RS
authors.lastname: Maskey
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Myoung Shin
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Bennett
authors.initials: B
authors.lastname: Childs
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Liviu A
authors.initials: LA
authors.lastname: Malureanu
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Karthik B
authors.initials: KB
authors.lastname: Jeganathan
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Machida
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.affiliation: 1] Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA [2] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Yuichi J
authors.initials: YJ
authors.lastname: Machida
mesh_terms: D000818:Animals; D002100:Cachexia / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002386:Cataract / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D016922:Cellular Senescence / Q000235:genetics; D002843:Chromatin / Q000737:chemistry* / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D015870:Gene Expression; D005804:Genes, Lethal; D042822:Genomic Instability; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008141:Lordosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective; D011371:Progeria / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; C000602442:Spartan protein, mouse; C045073:Cre recombinase; D019426:Integrases