Ku80 deletion suppresses spontaneous tumors and induces a p53-mediated DNA damage response.
Ku80 facilitates DNA repair and therefore should suppress cancer. However, ku80(-/-) mice exhibit reduced cancer, although they age prematurely and have a shortened life span. We tested the hypothesis that Ku80 deletion suppresses cancer by enhancing cellular tumor-suppressive responses to inefficiently repaired DNA damage. In support of this hypothesis, Ku80 deletion ameliorated tumor burden in APC(MIN) mice and increased a p53-mediated DNA damage response, DNA lesions, and chromosomal rearrangements. Thus, contrary to its assumed role as a caretaker tumor suppressor, Ku80 facilitates tumor growth most likely by dampening baseline cellular DNA damage responses.
Holcomb
Valerie B
VB
Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207, USA.
Rodier
Francis
F
Choi
YongJun
Y
Busuttil
Rita A
RA
Vogel
Hannes
H
Vijg
Jan
J
Campisi
Judith
J
Hasty
Paul
P
D000818:Animals; D034961:Antigens, Nuclear / Q000502:physiology*; D002869:Chromosome Aberrations; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D017491:Genes, APC; D007421:Intestine, Small / Q000378:metabolism; D000072200:Ku Autoantigen; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D034961:Antigens, Nuclear; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen