BUB1 is a protein inside cells that acts as a quality control gatekeeper, ensuring the cell’s genetic material is correctly sorted during division. BUB1 is a serine/threonine kinase, meaning it adds phosphate groups to other proteins to regulate their activity. Its proper function is fundamental for maintaining genomic stability—the ability of cells to keep their chromosome number and structure intact across generations of cell division. When BUB1 malfunctions, it can lead to developmental disorders and the unchecked growth characteristic of cancer.
BUB1’s Role in Regulating Cell Division
BUB1 functions as a central component of the Spindle Assembly Checkpoint (SAC), a surveillance mechanism operating during mitosis. Before a cell divides, it must duplicate its chromosomes and precisely align them. BUB1 ensures that each duplicated chromosome is correctly attached to the spindle fibers, which are the cellular machinery responsible for pulling the chromosomes apart.
BUB1 acts as the sensor that monitors these attachments, localizing to structures on the chromosomes called kinetochores when they are not yet fully attached. As a kinase, BUB1 initiates a signaling cascade that sends a “wait” signal. This signal prevents the cell from proceeding to the next stage of division, called anaphase, until all chromosomes are perfectly aligned.
This “wait” signal is produced by BUB1 recruiting other checkpoint proteins, notably the Mad1-Mad2 complex and BUBR1, which together form an inhibitor. This complex blocks the Anaphase Promoting Complex/Cyclosome (APC/C), the molecular machine responsible for triggering chromosome separation. Halting the APC/C ensures a delay until physical tension confirms that all chromosomes are correctly positioned for equal segregation.
Once all chromosomes are properly attached, the BUB1 signal stops, the APC/C is released from inhibition, and the cell proceeds to separate the chromosomes equally. If BUB1 fails to function correctly, the cell may divide prematurely, resulting in daughter cells with an incorrect number of chromosomes, a condition known as aneuploidy.
Inherited Disorders Linked to BUB1 Dysfunction
Disruptions in the BUB1 gene can lead to rare, inherited conditions, highlighting the protein’s importance in early development. One severe genetic disorder is Mosaic Variegated Aneuploidy (MVA) syndrome, characterized by widespread aneuploidy, where different cells possess varying, abnormal numbers of chromosomes.
While MVA syndrome is most frequently associated with mutations in the related gene, BUB1B (BUBR1), mutations in the BUB1 gene itself also cause a form of the syndrome. These mutations are inherited in an autosomal recessive pattern, meaning an individual must inherit a non-functional copy from both parents. The resulting BUB1 protein is either less abundant or has reduced function, leading to a weakened SAC.
The compromised chromosome segregation during early cell divisions results in a body composed of cell populations with different chromosomal counts—the “mosaic” pattern. Clinically, MVA syndrome manifests with severe developmental issues, including microcephaly (small head size), growth retardation, and congenital anomalies. The most concerning feature is the high predisposition to childhood cancers, such as acute lymphoblastic leukemia and Wilms’ tumor, due to genomic instability.
How BUB1 Contributes to Cancer Development
BUB1 dysfunction is relevant in the development and progression of common, acquired cancers in adults. In most sporadic tumors, the BUB1 protein is frequently overexpressed, meaning cancer cells produce much more of the protein than normal cells. This overexpression is observed in various malignancies, including breast, colorectal, gastric, and lung cancers.
Paradoxically, BUB1’s excessive presence promotes cancer by causing a specific failure in chromosome segregation. When BUB1 is overexpressed, it can lead to the hyperactivation of other mitotic regulators, such as the Aurora B kinase, which disrupts chromosome alignment. This leads to the formation of unstable attachments between the chromosomes and the spindle fibers.
The resulting mistakes in chromosome sorting generate Chromosomal Instability (CIN), a defining feature of many tumors where cells continuously gain or lose entire chromosomes. CIN drives tumorigenesis by creating a genetically diverse and unstable cancer cell population. These adaptable cells can acquire mutations that promote growth, resist chemotherapy, and allow for metastasis.
The level of BUB1 overexpression often correlates with a more aggressive disease and a poorer clinical prognosis. This suggests that the overabundance of BUB1 provides a selective advantage to the tumor cells, enabling them to evolve rapidly and evade treatment. BUB1 is considered an oncogene, a gene that can cause cancer when overexpressed or mutated.
BUB1 as a Target for Future Therapies
BUB1 dysregulation and its link to cancer progression has positioned the protein as a target for new therapeutic strategies. Since BUB1 is a serine/threonine kinase, it can be inhibited by small-molecule drugs that block its enzymatic activity. Research is focused on developing BUB1 inhibitors that selectively target and shut down the overactive protein in cancer cells.
The goal of BUB1 inhibition is to exploit the cancer cell’s dependence on its flawed SAC mechanism. By disrupting BUB1, researchers aim to push the unstable cancer cells past a tipping point, leading to catastrophic chromosome missegregation and cell death. Preclinical studies have shown that BUB1 inhibitors can sensitize tumor cells to existing treatments like chemotherapy and radiation, making them more effective.
BUB1 levels are also being investigated as a prognostic and predictive biomarker. High BUB1 expression is associated with worse survival rates in several cancer types, suggesting it can be used to predict disease outcome. Monitoring BUB1 levels might help determine which patients are most likely to respond to therapies that target the mitotic checkpoint, allowing for personalized treatment plans.