Within our cells, countless proteins work to maintain health and order. One such protein, BubR1, acts as a guardian of cellular integrity, functioning as a quality control manager for cell division. Its primary responsibility is to ensure that when a cell divides, its genetic information is copied and distributed with perfect accuracy. This process is constantly occurring throughout the body, from development to the replacement of old tissues, making the protein’s proper function a necessity for healthy tissues.
The Role of BubR1 in Cell Division
Cell division, known as mitosis, is how a cell replicates its chromosomes and divides to form two identical daughter cells. To prevent errors, cells use a safety mechanism called the spindle assembly checkpoint (SAC). The SAC verifies that every chromosome is correctly attached to a structure called the mitotic spindle before division proceeds.
The mitotic spindle is a set of cellular ropes, or microtubules, that extend from opposite poles of the cell. These ropes attach to a specific point on each chromosome, called the kinetochore. BubR1 is a component of the SAC, stationing itself at these kinetochores. Here, it senses whether the attachments between the chromosomes and the spindle are stable and under the correct tension.
If even a single chromosome is not properly attached, BubR1 sends out a “stop” signal. This signal blocks a protein complex called the anaphase-promoting complex/cyclosome (APC/C), which gives the “go-ahead” for division. By inhibiting the APC/C, BubR1 pauses the process, giving the cell time to correct faulty attachments. Only when all chromosomes are securely connected and aligned does BubR1 cease its signal, allowing the cell to complete its division.
This oversight ensures that each new daughter cell receives a complete and correct set of chromosomes. BubR1 acts as both a sensor and a communicator, translating the physical state of chromosome attachment into a chemical signal that controls the timing of cell division.
Consequences of BubR1 Malfunction
If BubR1 does not function correctly, the spindle assembly checkpoint can fail. This allows a cell to divide with improperly attached chromosomes, resulting in an unequal distribution of chromosomes, a condition known as aneuploidy. Aneuploidy means the daughter cells will have an abnormal number of chromosomes—either too many or too few.
This genetic imbalance is a hallmark of many cancers and can drive tumor development. Cells with an incorrect chromosome count often behave erratically, with disrupted growth signals and an inability to undergo programmed cell death. This genomic instability due to BubR1 malfunction can fuel cancer progression.
Mutations in the BUB1B gene, which provides instructions for making the BubR1 protein, are linked to specific diseases. One rare condition is Mosaic Variegated Aneuploidy (MVA) syndrome. Individuals with MVA have widespread aneuploidy, leading to developmental issues, a predisposition to cancer, and features of premature aging.
The connection between faulty BubR1, aneuploidy, and cancer shows how a breakdown in a cellular process can lead to disease. Research using mouse models has demonstrated that reduced levels of BubR1 lead to an increased incidence of aneuploidy and a higher susceptibility to cancer. These findings underscore the protein’s role in preventing cancerous growth.
BubR1’s Connection to the Aging Process
BubR1 is also connected to the natural process of aging. This connection relates to a gradual decline in the amount of BubR1 protein produced in cells as an organism gets older. Studies have documented that BubR1 expression levels decrease with age in various tissues in mammals.
This age-related reduction in BubR1 makes the spindle assembly checkpoint less efficient. Consequently, older cells are more prone to errors during division, leading to an increased rate of aneuploidy. This accumulation of chromosomally abnormal cells is thought to contribute to the functional decline and disease susceptibility associated with aging.
Laboratory studies support this connection. Mice engineered to have low levels of BubR1 exhibit many signs of premature aging, including cataracts, loss of subcutaneous fat, and a shortened lifespan. Conversely, mice genetically modified to produce higher levels of BubR1 show a delay in age-related deterioration and live longer, healthier lives.
This suggests that maintaining robust levels of BubR1 may help counteract some cellular damage that accumulates over time. The decline in BubR1 appears to be a natural part of aging, contributing to increased genomic instability in older tissues and making the cell’s quality control system less stringent.
BubR1 in Medical Research and Treatment
BubR1’s role in cellular health has made it a focus in medical research, particularly in oncology, where it presents a paradox. On one hand, low levels of BubR1 can lead to aneuploidy and promote the initial formation of tumors. This occurs because a weakened spindle assembly checkpoint allows genetically unstable cells to survive and evolve into cancer.
Once a tumor is established, the situation often reverses. Many aggressive cancer cells, characterized by chaotic and rapid division, become highly dependent on BubR1 to survive. Their division process is so unstable that they require a functional spindle assembly checkpoint to prevent catastrophic errors that would lead to their own death. This dependency creates a vulnerability that researchers hope to exploit.
This dependency has led to the development of drugs that inhibit BubR1. The goal is to selectively target and kill cancer cells by disabling the checkpoint they rely on for survival. By inhibiting BubR1, these drugs cause fatal division errors in unstable cancer cells while having a lesser effect on healthy cells.
BubR1 levels can also serve as a prognostic marker. In several types of cancer, including ovarian and breast cancer, the amount of BubR1 protein in tumor cells correlates with patient outcomes. High levels of BubR1 are often associated with more aggressive tumors and a poorer prognosis, which can help clinicians predict the disease course and guide treatment decisions.