BubR1 kinase: protection against aneuploidy and premature aging

Abstract

The multidomain protein kinase BubR1 is a central component of the mitotic spindle assembly checkpoint (SAC), an essential self-monitoring system of the eukaryotic cell cycle that ensures the high fidelity of chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bi-oriented on the mitotic spindle. We discuss the roles of BubR1 in the SAC and the implications of BubR1-mediated interactions that protect against aneuploidy. We also describe the emerging roles of BubR1 in cellular processes that extend beyond the SAC, discuss how mice models have revealed unanticipated functions for BubR1 in the regulation of normal aging, and the potential role of BubR1 as therapeutic target for the development of innovative anticancer therapies.

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

“…OGG1 (8-oxoguanine glycosylase) is a DNA glycosylate that repairs 8-hydroxyguanine (oh8Gua), a highly mutagenic oxidative DNA damage (89)(90)(91), and methyl-CpG binding domain 4 (Mbd4) is a DNA glycosylate involved in DNA demethylation via the pathway (92,93). BubR1-insufficient mice have similarly been used to study accelerated aging and senescence that results from chronic DNA damage signaling (94,95).…”

Chromosomal instability: A common feature and a therapeutic target of cancer

“…BubR1 declines sharply with age [130], and mouse models with reduced expression of BubR1 show aneuploidy [131]. Intriguingly, these mice were reported to have shorter life spans and more aging-associated phenotypes such as cataracts, and reduced skeletal muscle and fat [130,132]. In contrast, overexpression of BubR1 resulted in a longer life span and reduced aging-associated phenotypes [133].…”

The progeroid gene BubR1 regulates axon myelination and motor function

“…BubR1 is a core component of the spindle assembly checkpoint that times sister chromosome separation at anaphase onset with attachment of all chromosomes to the biplor spindle to ensure accurate chromosome segregation over the two daughter cells. As a multi-functional mitotic regulator, BubR1 is implicated in the proper timing of mitosis through APC/C Cdc20 signaling, kinetochore-microtubule attachment, and repair of merotelic and synthelic attachment errors through its role in the “attachment error correction machinery” [6, 7]. BubR1 is unique among mitotic regulators in that it is implicated in the development of aging-like pathologies [8, 9].…”