Study reveals how cancer cells bypass timing controls during division.
Cancer cells depend on fast and orderly division to keep growing, but that process can become risky when the timing of cell division stretches longer than normal. Healthy cells have a built-in way to sense when this process takes too long. When the delay reaches a certain point, a stress switch turns on and stops the cycle, keeping the damaged cells from dividing any further. In some cases, this switch can even push the troubled cells toward death. A research team at the Okinawa Institute of Science and Technology reported new findings describing how some cancers dodge this safeguard by losing their internal sense of timing, allowing division to continue when it should have stopped.
The group focused on a protein called USP28, which plays a part in the timing response. USP28 joins with other proteins to help steady p53, a well-known guardian in human cells. Under normal conditions, p53 is made all the time but breaks down too quickly to build up. When damage or stress appears, p53 becomes steady enough to gather in larger amounts. Once it reaches a high enough level, it signals the cell to pause or shut down division entirely. This prevents mistakes from spreading. When this support is disrupted, cells can slip past the normal checks and continue dividing, which is common in cancer.
In the new study, the team carefully mapped the parts of USP28 that allow it to connect with its partner proteins. They identified the molecular sections needed to hold the complex together, along with small changes—called mutations—that can weaken or break those links. When the researchers examined cancer-related versions of USP28, many of those changes appeared near the end of the protein chain, a region shaped by a group called a carboxyl. These changes kept USP28 from holding its partner proteins in place, leaving p53 unstable and unable to slow down division. With this safety step knocked out, cells continued splitting even when they lingered too long in the division stage.
To reach these conclusions, the team combined real-time imaging, single-cell tracking, and advanced structural modeling tools. This blend of live and predicted models helped them narrow down the exact areas of USP28 responsible for its role in the timing system. The work builds on years of earlier studies from the same group, all centered on how cells judge the length of division and decide when it has gone on too long. Many pieces of that timing puzzle remain unsolved, including how a cell measures passing minutes and what signals mark the cutoffs that trigger the internal alarm.
Even with those unknowns, the results give scientists more detail on how certain cancers continue dividing despite stress. Many cancer treatments already target the division stage, including long-used drugs designed to freeze cells that divide quickly. Knowing more about how the division timing system can be disrupted may guide the development of updated drugs or help determine which treatments may work best for tumors with specific protein changes.
The findings highlight how small changes in a single protein can influence the entire division process. By showing how USP28 mutations break the link that steadies p53, the study offers a clearer picture of why certain cancers grow unchecked. While the full timing system remains only partly understood, this new information gives researchers more tools to keep building toward future treatment options that take advantage of these weaknesses.
Sources:
Study shines new light on how cancer avoids the mitotic stopwatch pathway
Cancer-associated USP28 missense mutations disrupt 53BP1 interaction and p53 stabilization
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