Cancer susceptibility genes have been classified into two groups: gatekeepers and caretakers1. Gatekeepers are genes that control cell proliferation and death, whereas caretakers are DNA repair genes whose inactivation leads to genetic instability. Abrogation of both caretaker and gatekeeper function markedly increases cancer susceptibility. Although the importance of Ku80 in DNA double-strand break repair is well established, neither Ku80 nor other components of the non-homologous end-joining pathway are known to have a caretaker role in maintaining genomic stability. Here we show that mouse cells deficient for Ku80 display a marked increase in chromosomal aberrations, including breakage, translocations and aneuploidy. Despite the observed chromosome instabilities, Ku80-/- mice have only a slightly earlier onset of cancer2,3. Loss of p53 synergizes with Ku80 to promote tumorigenesis 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 amplifications involving IgH and c-Myc, reminiscent of Burkitt's lymphoma. We conclude that Ku80 is a caretaker gene that maintains the integrity of the genome by a mechanism involving the suppression of chromosomal rearrangements.
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We thank A. Singer, R. Hodes, A. Bhandoola, E. Besmer and S. Sharrow for comments on the manuscript and helpful discussions; K. Huppi, B. Malynn and R. Riblet for probes; and D. Liewehr, S. Steinberg and T. Brotz for assistance. M.C.N. is an investigator of the Howard Hughes Medical Institute. A.N. was supported in part by an award from the Arthritis Foundation.
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Experimental Hematology (2019)
Genome Instability & Disease (2019)
The American Journal of Human Genetics (2019)
Cellular and Molecular Life Sciences (2019)