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 and Yuichi J. Machida ()
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Reeja S. Maskey: Mayo Clinic
Myoung Shin Kim: Mayo Clinic
Darren J. Baker: Mayo Clinic
Bennett Childs: Mayo Clinic
Liviu A. Malureanu: Mayo Clinic
Karthik B. Jeganathan: Mayo Clinic
Yuka Machida: Mayo Clinic
Jan M. van Deursen: Mayo Clinic
Yuichi J. Machida: Mayo Clinic

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6744

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