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Published 13 February 2006. doi:10.1083/jcb.200507081
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 4, 529-540
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Article

 Early aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice

Darren J. Baker1,2, Karthik B. Jeganathan1,2, Liviu Malureanu1,2, Carmen Perez-Terzic3,4, Andre Terzic3,4, and Jan M.A. van Deursen1,2

1 Department of Pediatric and Adolescent Medicine, 2 Department of Biochemistry and Molecular Biology, 3 Department of Medicine, and 4 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905

Correspondence to Jan M.A. van Deursen: vandeursen.jan{at}mayo.edu

Aging is a highly complex biological process that is believed to involve multiple mechanisms. Mice that have small amounts of the mitotic checkpoint protein BubR1 age much faster than normal mice, but whether other mitotic checkpoint genes function to prevent the early onset of aging is unknown. In this study, we show that several aging-associated phenotypes appear early in mice that are double haploinsufficient for the mitotic checkpoint genes Bub3 and Rae1 but not in mice that are single haploinsufficient for these genes. Mouse embryonic fibroblasts (MEFs) from Bub3/Rae1 haploinsufficient mice undergo premature senescence and accumulate high levels of p19, p53, p21, and p16, whereas MEFs from single haploinsufficient mice do not. Furthermore, although BubR1 hypomorphic mice have less aneuploidy than Bub3/Rae1 haploinsufficient mice, they age much faster. Our findings suggest that early onset of aging-associated phenotypes in mice with mitotic checkpoint gene defects is linked to cellular senescence and activation of the p53 and p16 pathways rather than to aneuploidy.

Abbreviations used in this paper: APC, anaphase-promoting complex; DMBA, dimethylbenzanthrene; MEF, mouse embryonic fibroblast; MVA, mosaic variegated aneuploidy; NEBD, nuclear envelope breakdown; PI, propidium iodide; PMSCS, premature sister chromatid separation; SA, senescence associated.


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Aneuploidy does not equal aging
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