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Description
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Ku Antigen (DNA-dependent DNA helicase) is a heterodimer (of 72 and 87 kDapolypeptides) which contributes to genomic integrity through its ability to bind DNAdouble-strand breaks and facilitate repair by the nonhomologous end-joining pathway. ADNA double-strand break is a major lesion that destroys the integrity of the DNA molecule.Such damage is introduced by ionizing radiation. Ku binds to free double-stranded DNAends and is the DNA-binding component of the DNA-dependent protein kinase. Thus, theKu protein is involved in DNA repair and in V(D)J recombination, and theKu-DNA-dependent protein kinase complex may have a role in those same processes. Ku70and Ku80 share a common topology and form a dyad-symmetrical molecule with apreformed ring that encircles duplex DNA. The binding site can cradle 2 full turns of DNAwhile encircling only the central 3-4 base pairs. Ku makes no contacts with DNA bases andfew with the sugar-phosphate backbone, but it fits sterically to major and minor groovecontours so as to position the DNA helix in a defined path through the protein ring. Thesefeatures are well designed to structurally support broken DNA ends and to bring the DNAhelix into phase across the junction during end processing and ligation. Mouse cellsdeficient for Ku80 display a marked increase in chromosomal aberrations, includingbreakage, translocations, and aneuploidy. Despite the observed chromosome instabilities,Ku80 -/- mice have only a slightly earlier onset of cancer. Loss of p53 synergizes with Ku80to promote tumorigenesis such that all Ku80 -/- and p53 -/- mice succumb to disseminatedpro-B-cell lymphoma before 3 months of age. The p70/p80 complex binds to the ends ofdouble-stranded DNA in a cell cycle-dependent manner, being associated withchromosomes of interphase cells, followed by complete dissociation from the condensingchromosomes in early prophase. Some patients with systemic lupus erythematosus producevery large amounts of autoantibodies to p70 and p80. The autoantibody has been found inpatients with autoimmune thyroid disease (Graves disease) as well as in those with lupus.
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