Hidden cell division regulator opens door to new anti-cancer therapies
Each time a cell divides, it must accurately segregate its chromosomes to avoid errors that can lead to disease. To safeguard against such errors, cells use a safety system known as the spindle assembly checkpoint(opens in new window) (SAC). This mechanism ensures all the chromosomes are securely attached to the spindle before the cell proceeds with division. If something goes wrong, the checkpoint acts like a brake, stopping the cell from moving forward. Defects in this process can lead to genomic instability, a hallmark of cancer.
A closer look at a key cell division protein
Undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA)(opens in new window) programme, the SpinSAC project set out to better understand this SAC mechanism which is of particular interest for cancer drugs that disrupt cell division. The work focused on the hSpindly protein and investigated its role in SAC regulation. More specifically, the MSCA research fellow Mar Mora-Santos aimed to map key phosphorylation(opens in new window) sites on hSpindly and study their importance through engineered mutant DNA constructs. The ultimate goal was to decipher how these modifications affect recruitment of SAC proteins and how they influence cell responses to drug treatment. Researchers employed a range of advanced techniques to track the protein in live cells such as high-resolution microscopy and biochemical methods to detect changes in protein structure. By altering specific residues of hSpindly, researchers were able to observe how protein behaviour changes and how this affects the cell’s ability to respond to problems during division. “We discovered that hSpindly helps control the checkpoint, especially by recruiting other important proteins to the right place during cell division,” says Mora-Santos.
Implications for cancer therapies
One of the most important findings of the SpinSAC project was that hSpindly can help activate the checkpoint using a different route than previously known through the RZZ pathway(opens in new window). This means that cells may have more than one way of pausing division when things go wrong. “This discovery adds a whole new layer of understanding to how the checkpoint works,” highlights Mora-Santos. The team also found that phosphorylation-deficient hSpindly impaired SAC and was linked to greater resistance to taxanes – chemotherapy drugs used to treat various cancers by inhibiting cell division (mitosis). This suggests that hSpindly could serve as a biomarker for predicting patients’ response to treatment. Moreover, it could be used as a target for new drugs to restore sensitivity in resistant cancers.
From bench to bedside
Looking ahead, the investigator wants to make the findings clinically useful. For this reason, they plan to identify key enzymes implicated in protein phosphorylation that regulate hSpindly during mitosis. They also intend to test hSpindly phosphorylation status in in vivo tumour models and patient samples to validate its biomarker potential. “Understanding which enzymes modify hSpindly will be essential to reveal how its dynamics influence SAC activation and drug response,” emphasises Mora-Santos. Overall, SpinSAC has made an important contribution to our understanding of how cells manage division and how this process can be influenced to improve cancer treatment.
