Colonic tumorigenesis in BubR1 ^+/– Apc ^{Min /+} compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability

Abstract

Faithful chromosome segregation is essential for the maintenance of genetic stability during cell division and it is at least partly monitored by the spindle checkpoint, a surveillance mechanism preventing the cell from prematurely entering anaphase. The adenomatous polyposis coli (Apc) gene also plays an important role in regulating genomic stability, as mutations of Apc cause aneuploidy. Here we show that whereas Apc Min/؉ mice developed many adenomatous polyps, mostly in the small intestine, by 3 mo of age; BubR1 ؉/؊ Apc Min/؉ compound mutant mice developed 10 times more colonic tumors than Apc Min/؉ mice. The colonic tumors in BubR1 ؉/؊ Apc Min/؉ mice were in higher grades than those observed in Apc Min/؉ mice. Consistently, BubR1 ؉/؊ Apc Min/؉ murine embryonic fibroblasts (MEFs) contained more ␤-catenin and proliferated at a faster rate than WT or BubR1 ؉/؊ MEFs. Moreover, BubR1 ؉/؊ Apc Min/؉ MEFs slipped through mitosis in the presence of nocodazole and exhibited a higher rate of genomic instability than that of WT or BubR1 ؉/؊ or Apc Min/؉ MEFs, accompanied by premature separation of sister chromatids. Together, our studies suggest that BubR1 and Apc functionally interact in regulating metaphase-anaphase transition, deregulation of which may play a key role in genomic instability and development and progression of colorectal cancer.polyposis ͉ genetic instability ͉ colon cancer ͉ spindle checkpoint ͉ mitosis

BubR1 is involved in regulation of DNA damage responses

“…Mutations in BubR1 have been detected in colonic cancer (Cahill et al, 1998). Our mouse genetic study shows that haplo-insufficiency of BubR1 results in enhanced genomic instability and development of cancer in lung and colon (Dai et al, 2004;Rao et al, 2005). Consistently, a recent study shows that a compromised BubR1 activity due to specific germline mutations causes aneuploidy, infertility and/or early onset of malignancies (Hanks et al, 2004), strongly suggesting that spindle checkpoint failure is an underlying cause for the development of certain diseases.…”

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

“…C57BL/6‐based wild‐type (WT), Sgo1 −/+ (Rao et al., 2016; Yamada et al., 2012, 2015, 2016), and BubR1 −/+ (Dai et al., 2004; Rao et al., 2005) mice were bred and maintained in a pathogen‐free rodent barrier facility without treatment for 24–25 months (an observational study). Surviving animals were euthanized and organs were collected following our standard operating procedures (Yamada et al., 2012).…”

“…BubR1 −/+ mice showed mitotic slippage in the cells and were colon cancer‐prone (Dai et al., 2004; Rao et al., 2005), and BubR1 H/H hypomorphic mice were identified as a model for premature aging (Baker et al., 2004). Neuronal cell division and axon growth were inhibited by siRNA‐mediated BubR1 knockdown in the mouse brain (Yang et al., 2017).…”

Cytokinesis-block micronucleus cytome assay

“…For example, CpG island hypermethylation of mitotic spindle check point genes such as APC, BUBR1 and hCDC4 could reduce their expression and therefore increase the possibility of chromosome malsegregation leading to MN formation 47,48 . Silencing or loss of function of ATM, FANC and BRCA1 or BRCA2 genes involved in DNA repair could also result in higher baseline MN frequencies in human cells [49][50][51] .…”