Understanding the Centromere, the Key to Cell Division Maintenance

A centromere is a specialized location in the DNA that functions as the control centre of cell division and is maintained, unchanged, across generations of cells. It is characterized by a special protein, called centromeric protein A (CENP-A), which marks the centromere and mobilizes other players necessary for cell division. “One of the fundamental questions of life replication is: what is the mechanism that allows this structure (the CENP-A marker) to exactly restore itself at every cell cycle?”, says Prof. Dr. Andrea Musacchio from the Max Planck Institute of Molecular Physiology in Dortmund. Musacchio and his team have now been able to elucidate at the molecular level the exact mechanism that regulates the replenishment of the centromere with CENP-A. They used a set of biochemical techniques to infer how the protein called Polo-like kinase 1 (PLK1) regulates the assembly of the machinery responsible for CENP-A reloading.

A cascade of events

“We closed a gap in our knowledge that was open for 10 years,” says Duccio Conti, a postdoc in the Musacchio group and first author of the publication. In healthy DNA replication, at first, each new chromosome gets half of CENP-A proteins per centromere, which is replenished shortly after division - that process is completely unregulated in cancer cells. In 2014, another group found out that while one enzyme named CDK1 prevents the loading of CENP-A during most of the cell cycle, at a distinct time in the cell cycle the enzyme PLK1 promotes the refilling. Yet the precise molecular actions of PLK1 were unknown.

PLK1 is involved in many processes inside the cell, hence the usual approach of inhibiting it altogether would have disrupted its functioning. “The main challenge was to isolate only the specific function of PLK1 related to CENP-A reloading,” says Conti. MPI scientists building on earlier work reconstituted PLK1 and the whole refilling machinery in the test tube, and introduced mutations in specific points of the proteins to discern if and how they were involved in the process. They then confirmed their findings in cell, using cell biology essays.

As it turns out “PLK1 binds to one of the components of the restocking apparatus (a complex of four proteins), to make the arm of one of them open up and let the final element of the machinery bind, the chaperon protein HJURP which keeps CENP-A soluble and stable in the cytoplasm,” says Conti. PLK1 initiates the cascade of events by inducing a series of chemical changes (phosphorylation) and conformational changes in the nearby proteins of the machinery. “The discovery”, adds Conti, “paves the way for new questions about PLK1 and its involvement in regulating the insertion of new CENP-A proteins into the centromere.”

Reference: Conti D, Verza AE, Pesenti ME, et al. Role of protein kinase PLK1 in the epigenetic maintenance of centromeres. Science. 2024;385(6713):1091-1097. doi: 10.1126/science.ado5178

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