When we talk about memory in biology, we tend to focus on the storage of information within the brain and neurons. However, there are many other memories that remain within our cells. Cells remember their developmental history, such as whether they have been exposed to pathogens. And that raises questions that are difficult to answer. How does something as basic as a cell retain information across multiple divisions?
There is no one answer, and the details are often very difficult to unravel. But scientists have now elucidated one memory system in detail. Cells can remember when their parent cells had a hard time dividing. This is a problem often associated with DNA damage and cancer. And if the problem is severe enough, her two cells resulting from the division will stop dividing.
set timer
In multicellular organisms, cell division is very carefully controlled. Uncontrolled division is a hallmark of cancer. But mutations can occur if there are problems with individual segments of division, such as copying DNA, repairing damage, or ensuring each daughter cell acquires the appropriate number of chromosomes. Therefore, the process of cell division includes many checkpoints where the cell makes sure everything is working properly.
But if a cell can pass all the checkpoints, it’s probably fine, right? After all, it’s not perfect.
Mitosis is the part of cell division in which duplicate chromosomes are separated into each daughter cell. Spending too much time in mitosis means your chromosomes are damaged, which can cause problems down the road. Previous studies have also found that when mitosis takes too long, some cells from the retina register, causing daughter cells to stop dividing.
This new study, conducted by a team of researchers in Okinawa, Japan, and San Diego, begins by showing that this behavior is not limited to retinal cells and appears to be a general response to delayed mitosis. . Careful timing experiments showed that the longer a cell attempts to undergo mitosis, the more likely the daughter cells will stop dividing. Researchers call this system the “mitotic stopwatch.”
So how does a cell operate a stopwatch? It’s not like you can ask Siri to set a timer. Siri is primarily stuck processing nucleic acids and proteins.
As with many things related to cell division, the answer turns out to come down to a protein called p53. This is a protein that is key to many pathways that detect damage to cells and stop cells from dividing if there is a problem. (You may recall recent coverage of elephant stem cell development.)
Stopwatch made of protein
The researchers found that while mitosis is underway, p53 begins to appear in a complex with two other proteins (ubiquitin-specific protease 28 and the creatively named p53-binding protein 1). discovered. If you mutate one of the proteins that prevents this complex from forming, the mitotic stopwatch stops ticking. This three-protein complex begins to accumulate to significant levels only when mitosis takes longer than normal. It also remains stable after formation, so it can be passed on to daughter cells once cell division is complete.
So why does this complex form only when mitosis takes longer than normal? The key turns out to be proteins called kinases, which bind phosphates to other proteins. Researchers screened chemicals that inhibit specific kinases that are activated during mitosis and DNA repair, and discovered the specific kinases required for the mitotic stopwatch. In the absence of this kinase (PLK1, interestingly), the three protein complex does not form.
So researchers believe that a stopwatch works like this: During mitosis, the kinase slowly attaches a phosphate to one of the proteins, allowing it to form a three-protein complex. If mitosis is completed early enough, the levels of this complex are not very high and have no effect on the cell. However, as mitosis progresses more slowly, the complex begins to accumulate, and the complex is stable enough that it is still present within both daughter cells. The presence of this complex helps stabilize the p53 protein and, when present at high enough levels, can arrest future cell division.
Consistent with this idea, all three proteins in the complex are tumor suppressors, meaning that mutations in these proteins increase the likelihood of tumor formation. The researchers found that the mitotic stopwatch was frequently defective in tumor samples.
So, in this way, each individual cell is able to store one of its memories, the memory of the problem of cell division. However, the mitotic stopwatch is just one memory storage system; completely separate systems process different memories. And at the same time this is happening, numerous other pathways also influence her p53 activity. Thus, while the mitotic stopwatch can efficiently handle certain types of problems, it is integrated into many additional complex systems operating within the cell.
Science, 2024. DOI: 10.1126/science.add9528 (About DOI).
