Once we discuss reminiscences in biology, we are likely to give attention to the mind and the storage of data in neurons. However there are many different reminiscences that persist inside our cells. Cells keep in mind 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 elementary as a cell maintain on to info throughout a number of divisions?
There is no one reply, and the small print are actually troublesome to work out in lots of instances. However scientists have now labored out one reminiscence system intimately. Cells are capable of keep in mind when their father or mother had a troublesome time dividing—an issue that is usually related to DNA injury and most cancers. And, if the issues are substantial sufficient, the 2 cells that consequence from a division will cease dividing themselves.
Setting a timer
In multicellular organisms, cell division could be very fastidiously regulated. Uncontrolled division is the hallmark of cancers. However issues with the person segments of division—issues like copying DNA, repairing any injury, ensuring every daughter cell will get the correct variety of chromosomes—can result in mutations. So, the cell division course of contains plenty of checkpoints the place the cell makes positive every part has labored correctly.
But when a cell makes it via all of the checkpoints, it is presumably all good, proper? Not completely, 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 a variety of 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 brand new work, accomplished 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 common response to a gradual mitosis. Cautious timing experiments confirmed that the longer cells spent making an attempt to endure mitosis, the extra probably the daughter cells can be to cease dividing. The researchers time period this method a “mitotic stopwatch.”
So, how does a cell function a stopwatch? It is not like it may well 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 is a protein that is key to many pathways that detect injury to cells and cease them from dividing if there are issues. (Chances are you’ll recollect it from our current protection of the growth of elephant stem cells.)
A stopwatch manufactured from proteins
The researchers discovered that, whereas mitosis was occurring, p53 began exhibiting up in a fancy with two different proteins (ubiquitin-specific protease 28 and the creatively named p53-binding protein 1). In case you made mutations in one of many proteins that blocked this advanced from forming, the mitotic stopwatch stopped ticking. This three-protein advanced solely began constructing as much as vital ranges if mitosis took longer than ordinary, and it remained steady as soon as it fashioned in order that it will get handed on to the daughter cells as soon as cell division was accomplished.
So, why does this advanced kind solely when mitosis takes longer than ordinary? The important thing turned out to be a protein referred to as a kinase, which attaches a phosphate to different proteins. The researchers screened chemical substances that inhibit particular kinases which are lively throughout mitosis and DNA restore, and located a particular one which was wanted for the mitotic stopwatch. Within the absence of this kinase (PLK1, for the curious), the three-protein advanced would not kind.
So, the researchers suppose that the stopwatch appears like this: throughout mitosis, the kinase slowly attaches a phosphate to one of many proteins, permitting it to kind the three-protein advanced. If mitosis will get accomplished shortly sufficient, the degrees of this advanced do not get very excessive, and it has no impact on the cell. But when mitosis goes extra shortly, then the advanced begins increase, and it is steady sufficient that it is nonetheless round in each daughter cells. The existence of the advanced helps stabilize the p53 protein, permitting it to cease future cell divisions as soon as it is current at excessive sufficient ranges.
According to this concept, all three of the proteins within the advanced are tumor suppressors, that means that mutations in them make tumor formation extra probably. The researchers confirmed that the mitotic stopwatch was incessantly faulty in tumor samples.
So, that is how particular person cells handle to retailer certainly one of their reminiscences—the reminiscence of issues with cell division. The mitotic stopwatch, nevertheless, is simply one of many reminiscence storage programs, with fully separate programs dealing with totally different reminiscences. And, on the identical time that is occurring, a lot of different pathways additionally feed into the exercise of p53. So, whereas the mitotic stopwatch might effectively deal with one particular sort of drawback, it is built-in into a variety of extra, advanced programs working within the cell.
Science, 2024. DOI: 10.1126/science.add9528 (About DOIs).
