The Progeroid Phenotype of Ku80 Deficiency Is Dominant over DNA-PKCS Deficiency

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.

Do DNA Double-Strand Breaks Drive Aging?

“…Moreover, these mice display severe combined immunodeficiency, due to the defect in immunoglobulin class switch and V(D)J recombination (Zhu et al, 1996). Similar progeroid phenotypes were observed in mice deficient for Ku70 or DNA-PK cs (Espejel et al, 2004; Li et al, 2007; Reiling et al, 2014). However, Ku heterodimers do not act solely in NHEJ, but has other functions, most notably in telomere maintenance (Downs and Jackson, 2004).…”

Pathology of Mouse Models of Accelerated Aging

“…Some reports include thinning of the epidermis and atrophy of the panniculus carnosus muscle. Skin atrophy has been reported for multiple progeroid mouse models, including Col1α2-Cre +/- Sod2 -/ f mice, 145 Lmna L530P/L530P mice and Lmna G609G/G609G mice, 106,115 Klotho -/- mice, 167 Bub1b H/H mice, 9 Ku80 -/- mice, 69,154 and Dna-pk cs −/− mice 123 (Fig. 2, Table 6).…”

Genetic interaction between the non‐homologous end‐joining factors during B and T lymphocyte development: In vivo mouse models

“…Several complex mouse models have also revealed a lack of genetic interaction between different pairs of NHEJ genes (Figure 1). In particular, mice lacking Ku80 and either XLF ( Ku80 −/− Xlf −/− ), PAXX ( Ku80 −/− Paxx −/− ) 19 or DNA‐PKcs ( Ku80 −/− Dna‐pkcs −/− ) 48 are indistinguishable from Ku80 −/− mice, whereas Ku70 −/− Xlf −/− and Ku70 −/− Dna‐pkcs −/− mice are indistinguishable from Ku70 −/− littermates 40 . Finally, embryonic lethality of Lig4 −/− mice is not rescued by the inactivation of Paxx −/− ( Lig4 −/− Paxx −/− ) 19 (Figure 1).…”