BUBR1 Insufficiency in Mice Increases Their Sensitivity to Oxidative Stress

Abstract

Abstract. Background Budding uninhibited by benzimidazole-related 1 (BUBR1) is a core component of the spindle assembly checkpoint, which monitors whether or not sister chromatids are correctly separated during mitosis. Dysfunction of BUBR1 provokes chromosomal instability, thus leading to aneuploidy (1). Baker et al. generated mice with BubR1 gene mutation with various decreased expression levels of BubR1 due to combinations of wild-type, null, and hypomorphic BubR1 alleles (2-4). The mice that were homogeneous for the hypomorphic allele showed an early onset of aging phenotypes, such as short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat, impaired wound healing, and decreased vascular wall elasticity (2,4). Chromosomal instability, such as aneuploidy, frequently occurred in the cells derived from hypomorphic BubR1 mice, but few mice spontaneously died of cancer under normal conditions (2). Notably, Dai et al. reported that mice with the wild-type allele and null allele were susceptible to carcinogen-induced adenocarcinoma in the lungs and intestines (5), suggesting that aneuploidy caused by the decreased expression of BUBR1 might enhance carcinogeninduced tumorigenesis in mammals.We recently generated a new strain of hypomorphic BubR1 mice in which the expression of BUBR1 is reduced to 20% of the normal level. These low BUBR1-expressing mutant mice (termed BubR1 L/L mice) do not display apparent abnormalities, such as progeria, infertility, shortened lifespan, or structural anomaly in the tissue during growth and development, under normal conditions. Therefore, BubR1 L/L mice are particularly suitable for investigating the precise roles of BUBR1 in age-related diseases, including cancer. Using these mice, we previously demonstrated that decreased expression of BUBR1 completely inhibits intimal hyperplasia after carotid ligation by suppressing the 769 Τhis article is freely accessible online.

Gene expression in retinal ischemic post-conditioning

“…Bub1b is a component of the mitotic spindle checkpoint, which prevents sister chromatid separation during cell division. Abnormal Bub1b signaling has been implicated in premature aging, although to date, no studies have addressed its role in retina [35, 36]. MCM proteins control DNA unwinding.…”