Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice

Non‐homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double‐strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA‐PK complex, formed by the Ku86/70 heterodimer and the DNA‐PK catalytic subunit (DNA‐PKcs). Here, we report on the detailed life‐long follow‐up of DNA‐PKcs‐defective mice. Apart from defining a role of DNA‐PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA‐PKcs‐defective mice had a shorter life span and showed an earlier onset of ageing‐related pathologies than the corresponding wild‐type littermates. In addition, DNA‐PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA‐PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.