When we speak about recollections in biology, we are likely to deal with the mind and the storage of data in neurons. But there are many different recollections that persist inside our cells. Cells remember their developmental historical past, whether or not they’ve been uncovered to pathogens, and so forth. And that raises a query that has been difficult to reply: How does one thing as basic as a cell maintain on to info throughout a number of divisions?
There’s nobody reply, and the small print are actually tough to work out in lots of circumstances. But scientists have now labored out one reminiscence system intimately. Cells are in a position to remember when their guardian had a tough time dividing—an issue that is typically related to DNA injury and most cancers. And, if the issues are substantial sufficient, the 2 cells that end result from a division will cease dividing themselves.
Setting a timer
In multicellular organisms, cell division could be very rigorously regulated. Uncontrolled division is the hallmark of cancers. But issues with the person segments of division—issues like copying DNA, repairing any injury, ensuring every daughter cell will get the appropriate variety of chromosomes—can result in mutations. So, the cell division course of contains a lot of checkpoints the place the cell makes positive every part has labored correctly.
But if a cell makes it by way of all of the checkpoints, it is presumably all good, proper? Not totally, because it seems.
Mitosis is the portion of cell division the place the duplicated chromosomes get separated out to every of the daughter cells. Spending numerous time in mitosis can imply that the chromosomes have picked up injury, which can trigger issues sooner or later. And prior analysis discovered that some cells derived from the retina will register when mitosis takes too lengthy, and the daughter cells will cease dividing.
The new work, finished by a crew of researchers in Okinawa, Japan, and San Diego, began by exhibiting that this conduct wasn’t restricted to retinal cells—it appears to be a normal response to a gradual mitosis. Careful timing experiments confirmed that the longer cells spent attempting to bear mitosis, the extra doubtless the daughter cells could be to cease dividing. The researchers time period this technique a “mitotic stopwatch.”
So, how does a cell function a stopwatch? It’s not like it might probably ask Siri to set a timer—it is largely caught working with nucleic acids and proteins.
It seems that, like many issues relayed to cell division, the reply comes all the way down to a protein named p53. It’s a protein that is key to many pathways that detect injury to cells and cease them from dividing if there are issues. (You could recollect it from our latest protection of the event of elephant stem cells.)
A stopwatch fabricated from proteins
The researchers discovered that, whereas mitosis was occurring, p53 began exhibiting up in a posh with two different proteins (ubiquitin-specific protease 28 and the creatively named p53-binding protein 1). If you made mutations in one of many proteins that blocked this complicated from forming, the mitotic stopwatch stopped ticking. This three-protein complicated solely began constructing as much as vital ranges if mitosis took longer than common, and it remained steady as soon as it fashioned in order that it could get handed on to the daughter cells as soon as cell division was accomplished.
So, why does this complicated type solely when mitosis takes longer than common? The key turned out to be a protein known as a kinase, which attaches a phosphate to different proteins. The researchers screened chemical compounds that inhibit particular kinases which are energetic throughout mitosis and DNA restore, and located a selected one which was wanted for the mitotic stopwatch. In the absence of this kinase (PLK1, for the curious), the three-protein complicated would not type.
So, the researchers assume that the stopwatch seems to be like this: throughout mitosis, the kinase slowly attaches a phosphate to one of many proteins, permitting it to type the three-protein complicated. If mitosis will get finished rapidly sufficient, the degrees of this complicated do not get very excessive, and it has no impact on the cell. But if mitosis goes extra slowly, then the complicated begins increase, and it is steady sufficient that it is nonetheless round in each daughter cells. The existence of the complicated helps stabilize the p53 protein, permitting it to cease future cell divisions as soon as it is current at excessive sufficient ranges.
Consistent with this concept, all three of the proteins within the complicated are tumor suppressors, which means that mutations in them make tumor formation extra doubtless. The researchers confirmed that the mitotic stopwatch was incessantly faulty in tumor samples.
So, that is how particular person cells handle to retailer one in every of their recollections—the reminiscence of issues with cell division. The mitotic stopwatch, nonetheless, is simply one of many reminiscence storage programs, with utterly separate programs dealing with totally different recollections. And, on the identical time that is occurring, numerous different pathways additionally feed into the exercise of p53. So, whereas the mitotic stopwatch could effectively deal with one particular sort of drawback, it is built-in into numerous extra, complicated programs working within the cell.
Science, 2024. DOI: 10.1126/science.add9528 (About DOIs).