Ku, a DNA repair protein with multiple cellular functions?

Abstract

The Ku protein binds to DNA ends and other types of discontinuity in double-stranded DNA. It is a tightly associated heterodimer of ∼70 kDa and ∼80 kDa subunits that together with the ∼470 kDa catalytic subunit, DNA-PKcs, form the DNA-dependent protein kinase. This enzyme is involved in repairing DNA double-strand breaks (DSBs) caused, for example, by physiological oxidation reactions, V(D)J recombination, ionizing radiation and certain chemotherapeutic drugs. The Ku-dependent repair process, called illegitimate recombination or nonhomologous end joining (NHEJ), appears to be the main DNA DSB repair mechanism in mammalian cells. Ku itself is probably involved in stabilizing broken DNA ends, bringing them together and preparing them for ligation. Ku also recruits DNA-PKcs to the DSB, activating its kinase function. Targeted disruption of the genes encoding Ku70 and Ku80 has identified significant differences between Ku-deficient mice and DNA-PKcs-deficient mice. Although all three gene products are clearly involved in repairing ionizing radiation-induced damage and in V(D)J recombination, Ku-knockout mice are small, and their cells fail to proliferate in culture and show signs of premature senescence. Recent findings have implicated yeast Ku in telomeric structure in addition to NHEJ. Some of the phenotypes of the Ku-knockout mice may indicate a similar role for Ku at mammalian telomeres.