The progeroid phenotype of Ku80 deficiency Is dominant over DNA-PK CS deficiency

Erwin Reiling, Martijn E T Dollé, Sameh A. Youssef, Moonsook Lee, Bhawani Nagarajah, Marianne Roodbergen, Piet De With, Alain De Bruin, Jan H. Hoeijmakers, Jan Vijg, Harry Van Steeg, Paul Hasty

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Abstract

Ku80 and DNA-PKCS are both involved in the repair of double strand DNA breaks via the nonhomologous end joining (NHEJ) pathway. While ku80-/- mice exhibit a severely reduced lifespan and size, this phenotype is less pronounced in dna-pkcs -/- mice. However, these observations are based on independent studies with varying genetic backgrounds. Here, we generated ku80-/-, dna-pkcs -/- and double knock out mice in a C57Bl6/J*FVB F1 hybrid background and compared their lifespan, end of life pathology and mutation frequency in liver and spleen using a lacZ reporter. Our data confirm that inactivation of Ku80 and DNA-PKCS causes reduced lifespan and bodyweights, which is most severe in ku80-/- mice. All mutant mice exhibited a strong increase in lymphoma incidence as well as other aging-related pathology (skin epidermal and adnexal atrophy, trabacular bone reduction, kidney tubular anisokaryosis, and cortical and medullar atrophy) and severe lymphoid depletion. LacZ mutation frequency analysis did not show strong differences in mutation frequencies between knock out and wild type mice. The ku80-/- mice had the most severe phenotype and the Ku80-mutation was dominant over the DNA-PKCS-mutation. Presumably, the more severe degenerative effect of Ku80 inactivation on lifespan compared to DNA-PKCS inactivation is caused by additional functions of Ku80 or activity of free Ku70 since both Ku80 and DNA-PKCS are essential for NHEJ.

Original languageEnglish (US)
Article numbere93568
JournalPLoS One
Volume9
Issue number4
DOIs
StatePublished - Apr 16 2014

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lysyl-arginyl-alanyl-lysyl-alanyl-lysyl-threonyl-threonyl-lysyl-lysyl-arginine
Phenotype
phenotype
Mutation Rate
DNA
mice
mutation
Knockout Mice
Atrophy
Pathology
inactivation
Joining
atrophy
Mutation
Double-Stranded DNA Breaks
Lymphoma
Liver
Spleen
Pyruvate Kinase Deficiency of Red Cells
lymphoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Reiling, E., Dollé, M. E. T., Youssef, S. A., Lee, M., Nagarajah, B., Roodbergen, M., ... Hasty, P. (2014). The progeroid phenotype of Ku80 deficiency Is dominant over DNA-PK CS deficiency. PLoS One, 9(4), [e93568]. https://doi.org/10.1371/journal.pone.0093568

The progeroid phenotype of Ku80 deficiency Is dominant over DNA-PK CS deficiency. / Reiling, Erwin; Dollé, Martijn E T; Youssef, Sameh A.; Lee, Moonsook; Nagarajah, Bhawani; Roodbergen, Marianne; De With, Piet; De Bruin, Alain; Hoeijmakers, Jan H.; Vijg, Jan; Van Steeg, Harry; Hasty, Paul.

In: PLoS One, Vol. 9, No. 4, e93568, 16.04.2014.

Research output: Contribution to journalArticle

Reiling, E, Dollé, MET, Youssef, SA, Lee, M, Nagarajah, B, Roodbergen, M, De With, P, De Bruin, A, Hoeijmakers, JH, Vijg, J, Van Steeg, H & Hasty, P 2014, 'The progeroid phenotype of Ku80 deficiency Is dominant over DNA-PK CS deficiency', PLoS One, vol. 9, no. 4, e93568. https://doi.org/10.1371/journal.pone.0093568
Reiling E, Dollé MET, Youssef SA, Lee M, Nagarajah B, Roodbergen M et al. The progeroid phenotype of Ku80 deficiency Is dominant over DNA-PK CS deficiency. PLoS One. 2014 Apr 16;9(4). e93568. https://doi.org/10.1371/journal.pone.0093568
Reiling, Erwin ; Dollé, Martijn E T ; Youssef, Sameh A. ; Lee, Moonsook ; Nagarajah, Bhawani ; Roodbergen, Marianne ; De With, Piet ; De Bruin, Alain ; Hoeijmakers, Jan H. ; Vijg, Jan ; Van Steeg, Harry ; Hasty, Paul. / The progeroid phenotype of Ku80 deficiency Is dominant over DNA-PK CS deficiency. In: PLoS One. 2014 ; Vol. 9, No. 4.
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