DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation

Cancer susceptibility genes have been classified into two groups: gatekeepe rs and caretakers(1). Gatekeepers are genes that control cell proliferation and death, whereas caretakers are DNA repair genes whose inactivation lead s to genetic instability. Abrogation of both caretaker and gatekeeper funct ion markedly increases cancer susceptibility. Although the importance of Ku 80 in DNA double-strand break repair is well established, neither Ku80 nor other components of the non-homologous end-joining pathway are known to hav e a caretaker role in maintaining genomic stability. Here we show that mous e cells deficient for Ku80 display a marked increase in chromosomal aberrat ions, including breakage, translocations and aneuploidy. Despite the observ ed chromosome instabilities, Ku80(-/-) mice have only a slightly earlier on set of cancer(2,3). Loss of p53 synergizes with Ku80 to promote tumorigenes is such that all Ku80(-/-) p53(-/-) mice succumb to disseminated pro-B-cell lymphoma before three months of age. Tumours result from a specific set of chromosomal translocations and gene amplications involving IgH and c-Myc, reminiscent of Burkitt's lymphoma. We conclude that Ku80 is a caretaker gen e that maintains the integrity of the genome by a mechanism involving the s uppression of chromosomal rearrangements.