Changes in the level and distribution of Ku proteins during cellular senescence

Aging is associated with accumulation of genomic rearrangements consistent with aberrant repair of DNA breaks. We have shown previously that DNA repair by non-homologous end joining (NHEJ) becomes less efficient and more error-prone in senescent cells. Here, we show that the levels of Ku70 and Ku80 drop approximately twofold in replicatively senescent cells. Intracellular distribution of Ku also changes. In the young cells roughly half of Ku is located in the nucleus and half in the cytoplasm. In senescent cells the nuclear levels of Ku do not change, while the cytoplasmic Ku fraction disappears. Upon treatment with gamma-irradiation, in the young cells cytoplasmic Ku moved into the nuclear and membrane fractions, while no change in the Ku distribution occurred in senescent cells. Upon treatment with UVC Ku. moved out of the nucleus in the young cells, while most Ku remained nuclear in senescent cells. This suggests that the nuclear Ku in senescent cells is unable to respond to DNA damage. We hypothesize that overall decline in Ku levels changes in Ku intracellular distribution, and the loss of appropriate response of Ku to DNA damage in senescent cells contribute to the decline of NHEJ and to age-related genomic instability. (C) 2007 Elsevier B.V. All rights reserved.