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Lighting the way at the University of Edinburgh

The pioneering work of researchers from School of Biological Sciences at Edinburgh University reveals how unseen triggers orchestrate the first known steps of a key life process and can help offer clues to better ways to treat diseases like cancer.

As part of the renewal and repair processes that keep our bodies going, millions of new cells are made inside each of us every day through cell division.

Although it is one of the most fundamental processes in the biological world, the inner workings of its earliest known steps have remained shrouded in mystery.

A team led by Professor Bill Earnshaw and Dr Georg Kustatscher have used pioneering techniques to shed light on the first measurements taken inside cells as they begin to divide.

“Our study offers insight into the first, unprecedented steps of cell division,” says Professor Earnshaw. “It’s a process that’s essential for all plant and animal life on Earth, but there’s still so much about it that we don’t fully understand, especially what’s going on early on.”

All of people’s genetic information is organized into 23 chromosomes inside their cells. As good as DNA, chromosomes also contain protein molecules – many of them. In non-dividing cells, proteins move dynamically DNA to perform and regulate a range of functions, from controlling which genes are turned on or off to repairing damaged sections of DNA. The role that many of these proteins play in the early stages of cell division is less clear.

When a cell divides, its chromosomes must be carefully packed into compact packages to ensure that they are distributed equally between the two new cells that are created. Each chromosome is first replicated before the division process begins. It is only when replication is complete that what looks like a spaghetti-like jumble of threads compacts into rigid X-shaped rods in the center of the cell. When the cell begins to divide in two, a scaffolding of tubular structures allows molecular motors to drag one copy of each of the 23 chromosomes into the two newly formed cells.

But it doesn’t always go smoothly, as Kustatscher explains: “When millions and millions of cells are dividing, some mistakes will inevitably occur. Errors can lead to new cells that have too many or too few chromosomes, a characteristic known as aneuploidy. When occurring in embryonic cells, aneuploidy is usually fatal, but it is also a common feature of .

A better understanding of the precise way chromosomes are packed and moved into new cells – and the role proteins play in this – could offer important insights into what could be a key feature of a number of diseases. , says Earnshaw.

To dig deeper into this question, Earnshaw devised a method that would allow them to shed light on the very early stages of cell division.

A big challenge for studying cell division is that, at any given time, the cells in a laboratory petri dish will be at different stages of the division process. It is therefore very difficult to analyze what is happening at specific points in the process.

Earnshaw’s method, developed by his Japanese associate Dr Kumiko Samejima, involves genetically modifying chicken cells – which undergo a very similar process of division to humans – so that the onset of cell division can be blocked. using a drug. As soon as the drug is removed, the cells begin to divide rapidly and perfectly synchronized.

This allowed the researchers to use a powerful analytical machine, called a mass spectrometer, to detect which proteins were bound to chromosomes at the very start of cell division, and how these changed during the first 25 minutes of the process.

They tracked 2,500 of these proteins and found that hundreds of chromosomes broke off because their functions weren’t needed during cell division. At the same time, other proteins move through the cell and attach to the chromosomes, as they prepare to be separated into the new forming cells.

“What our results show is that by the time you can see under a microscope that the packing process of the chromosomes has started, there have already been thousands of changes in the proteins that attach to them,” explains Professor Earnshaw.

The team developed an app to help researchers study the proteins they identified and better understand their involvement in cell division. This, in turn, can reveal more key details about the precise mechanisms behind the early stages of the process.

The hope is that it could open up a new frontier of cell division research, and ultimately help facilitate the development of new therapies for diseases characterized by errors in the process, Earnshaw says. “As a fundamental process, cell division is implicated in a wide range of medical conditions in one way or another. By developing a resource that other scientists can use and exploit, we hope our work can serve a focal point for researchers around the world to collaborate to further unravel the inner workings of cell division.

Their research, published in the journal Molecular Cell, was funded by Welcome. An open access version of the article is available: Mapping invisible chromatin transactions of chromosomal remodeling in prophase

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