Proteins let cells bear in mind how nicely their final division went


After we speak about recollections in biology, we are inclined to give attention to the mind and the storage of data in neurons. However there are many different recollections that persist inside our cells. Cells bear 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 basic as a cell maintain on to data throughout a number of divisions?

There isn’t any one reply, and the main points are actually troublesome to work out in lots of instances. However scientists have now labored out one reminiscence system intimately. Cells are in a position to bear 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 end result from a division will cease dividing themselves.

Setting a timer

In multicellular organisms, cell division may be very rigorously 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 best variety of chromosomes—can result in mutations. So, the cell division course of consists of numerous checkpoints the place the cell makes positive all the things has labored correctly.

But when a cell makes it by all of the checkpoints, it is presumably all good, proper? Not fully, 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 plenty 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, executed by a crew of researchers in Okinawa, Japan, and San Diego, began by displaying that this conduct wasn’t restricted to retinal cells—it appears to be a normal response to a gradual mitosis. Cautious timing experiments confirmed that the longer cells spent attempting to endure mitosis, the extra seemingly the daughter cells can be to cease dividing. The researchers time period this technique a “mitotic stopwatch.”

So, how does a cell function a stopwatch? It isn’t like it will 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 right 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. (You might recollect it from our current protection of the growth of elephant stem cells.)

A stopwatch made from proteins

The researchers discovered that, whereas mitosis was occurring, p53 began displaying up in a fancy with two different proteins (ubiquitin-specific protease 28 and the creatively named p53-binding protein 1). When 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 important ranges if mitosis took longer than common, and it remained steady as soon as it shaped in order that it will get handed on to the daughter cells as soon as cell division was accomplished.

So, why does this complicated kind solely when mitosis takes longer than common? The important thing turned out to be a protein known as a kinase, which attaches a phosphate to different proteins. The researchers screened chemical substances that inhibit particular kinases which might be energetic throughout mitosis and DNA restore, and located a selected one which was wanted for the mitotic stopwatch. Within the absence of this kinase (PLK1, for the curious), the three-protein complicated does not kind.

So, the researchers suppose that the stopwatch seems like this: throughout mitosis, the kinase slowly attaches a phosphate to one of many proteins, permitting it to kind the three-protein complicated. If mitosis will get executed shortly sufficient, the degrees of this complicated do not get very excessive, and it has no impact on the cell. But when mitosis goes extra shortly, 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.

Per this concept, all three of the proteins within the complicated are tumor suppressors, that means that mutations in them make tumor formation extra seemingly. The researchers confirmed that the mitotic stopwatch was ceaselessly faulty in tumor samples.

So, that is how particular person cells handle to retailer certainly one of their recollections—the reminiscence of issues with cell division. The mitotic stopwatch, nonetheless, is simply one of many reminiscence storage methods, with utterly separate methods dealing with totally different recollections. 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 kind of drawback, it is built-in into plenty of further, complicated methods working within the cell.

Science, 2024. DOI: 10.1126/science.add9528  (About DOIs).

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