Dive into the fascinating world of cell division and discover how centromeres, the control centers of this process, are maintained across generations. Learn about the key role of the centromeric protein A (CENP-A) and the intricate mechanism regulated by the polo-like kinase 1 (PLK1) enzyme. Explore the implications of this discovery for understanding cancer cell division. Cell division, Centromere, Polo-like kinase 1
Uncovering the Centromere’s Central Role in Cell Division
The centromere is a specialized region within the DNA that acts as Division Control Central. Distinctly, this region is defined by a non-histone protein known as centromeric protein A (CENP-A) which orchestrates the recruitment of the machinery needed for successful segregation. So, how is this important structure maintained, and passed on, generation after generation of cells?
Scientists at the Max Planck Institute of Molecular Physiology in Dortmund, led by Prof. Dr. Andrea Musacchio, have now discovered how this process is controlled with utmost precision: Using a sophisticated regulatory mechanism ensuring that CENP-A will only be replenished once it has been partially degraded, i.e., after you are sure it’s time for something new! Johannes Graumann (left) and Ulrike Bauer infected plant cells with Y pseudotuberculosis and a marked YopE fusion protein, then isolated and fixed centrosomes to determine the location of the microinjected bacterial virulence factor using immunofluorescence. They used biochemical tools to prove that PLK1 is central to the process.
Revealing the Controlled Orchestration of CENP-A Reassembly
As described in Science, the team’s findings have filled one of our oldest gaps in knowledge on cell division. Surprisingly, the researchers found that the enzyme CDK1 was responsible for preventing the loading of CENP-A during most of the cell cycle, but at a particular time point in mitosis another enzyme — PLK1 — took over in driving replacement.
Since PLK1 has many cellular functions, the researchers needed to determine what aspect of PLK1 activity is critical in CENP-A reloading. By reconstituting the entire refilling machinery in vitro and inducing specific mutations, they then elucidated the exact molecular actions of PLK1.
The Pivotal Role of PLK1 in Maintaining Centromere Integrity
Specifically, the team learned that one of the components of the CENP-A replenishment machinery is a four-protein complex to which PLK1 binds. That kicks off a series of phosphorylation and allosteric changes in the surrounding proteins that permit the final machinery element, chaperone protein (HJURP98), to bind CENP-A and keep it soluble and stable in the cytoplasm.
This finding will have implications for the study of how centromere maintenance is tightly regulated in nature, suggesting new directions for cancer research as well. Most notably, the one type of dividing cell where this reloading process goes abnormal is cancerous cells, which are essentially engaging tumor-inducing behavior through uncontrolled division. By knowing that PLK1 facilitates this pathway, the researchers say it is possible to consider ways in which therapeutic strategies might be developed against the enzyme and its machinery.
