Spartan deficiency causes genomic instability and progeroid phenotypes

Reeja S Maskey; Myoung Shin Kim; Darren J Baker; Bennett Childs; Liviu A Malureanu; Karthik B Jeganathan; Yuka Machida; Jan M van Deursen; Yuichi J Machida

doi:10.1038/ncomms6744

Spartan deficiency causes genomic instability and progeroid phenotypes

Nat Commun. 2014 Dec 11:5:5744. doi: 10.1038/ncomms6744.

Authors

Reeja S Maskey¹, Myoung Shin Kim², Darren J Baker³, Bennett Childs¹, Liviu A Malureanu¹, Karthik B Jeganathan¹, Yuka Machida², Jan M van Deursen¹, Yuichi J Machida⁴

Affiliations

¹ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
² Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
³ Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
⁴ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cachexia / complications
Cachexia / genetics*
Cachexia / metabolism
Cachexia / pathology
Cataract / complications
Cataract / genetics*
Cataract / metabolism
Cataract / pathology
Cell Death
Cellular Senescence / genetics
Chromatin / chemistry*
Chromatin / pathology
Chromosomal Proteins, Non-Histone / deficiency
Chromosomal Proteins, Non-Histone / genetics*
DNA Replication*
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics*
Female
Fibroblasts / metabolism
Fibroblasts / pathology
Gene Dosage
Gene Expression
Genes, Lethal
Genomic Instability
Integrases / genetics
Integrases / metabolism
Lordosis / complications
Lordosis / genetics*
Lordosis / metabolism
Lordosis / pathology
Male
Mice
Mice, Knockout
Micronuclei, Chromosome-Defective
Progeria / complications
Progeria / genetics*
Progeria / metabolism
Progeria / pathology
Proliferating Cell Nuclear Antigen / genetics
Proliferating Cell Nuclear Antigen / metabolism
Signal Transduction

Substances

Chromatin
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Proliferating Cell Nuclear Antigen
Spartan protein, mouse
Cre recombinase
Integrases

Abstract

Publication types

MeSH terms

Substances

Grants and funding