Lord of the Rings – Cohesin and cancer

When the media talks about breakthroughs in cancer research, they often lead us to believe that a cure for thousands is around the corner. But the reality is rather different. When scientists use the word ‘breakthrough’ – and they rarely do – they tend to be talking about something less concrete but no less exciting – fundamental discoveries that change the way we view cancer.

One of our scientists – Professor Kim Nasmyth – recently made such a discovery.  But what was it all about?

Cell division and the cohesin connection
Our bodies need a constant supply of new cells, for growth, healing and to replace old, dead ones – particularly in places like our gut, skin and bone marrow. Cells are made by cell division – one cell divides to produce two ‘daughters’, in a process called mitosis.  Cancer occurs when this process goes wrong and runs out of control.

In a cell, genetic information is stored in the form of chromosomes – long molecules of DNA. So when a cell divides, it has to copy all of its chromosomes so that each daughter cell has a full complement of genes. Just before the cell divides, it contains a ‘double-dose’ of chromosomes, and these need to be separated as the cell splits in two.

So, in a remarkable feat of miniature engineering, the two sets of chromosomes are lined up along molecular scaffolding in the middle of the cell, then pulled apart to opposite sides of the cell as it divides. But the exact details of how this happens are still a bit of a mystery.

In trying to understand this critical process, scientists found that each chromosome pair is held together by a protein called cohesin.  And they discovered that when the cell is ready to divide, cohesin is somehow broken down, and the chromosomes are separated equally into the two new daughters.

If something goes wrong with this process, and cohesin doesn’t work properly, then the cell may die (if it cannot divide at all), or it may divide but share the chromosomes unequally between the daughter cells. If this happens, the new cells will either lack certain genes, or have extra copies – either of these situations is well known to lead to cancer.

Ring-shaped – but how does it work?
So we know that cohesin is a very important molecule, but it’s not clear exactly how it works. Cohesin is made up of three smaller molecular ‘building blocks’, forming a ring structure.  Researchers around the world have proposed various ideas to explain how it actually holds chromosomes together.

Some scientists have suggested that cohesin traps the chromosome pairs inside a ring, like a rubber band wrapped around drinking straws (the ‘ring model’).  But others think it acts like Blu-Tack, sitting between the chromosomes and sticking them together.

Obviously, these processes take place on a scale far too miniature to see the precise structure down a microscope, and the results of many experiments have been inconclusive – they could support either theory.

Sealing the ring
Professor Kim Nasmyth is a world expert in cohesin – in fact, he discovered it in 1997.  He was the one who first proposed the ring model, and has been working hard to find out whether it’s true.  To do this, he devised a simple experiment in yeast, which have circular chromosomes (human chromosomes are straight, like shoelaces).

Nasmyth and his team used clever molecular engineering techniques to produce a form of cohesin in which its building blocks could be permanently stuck together under specific circumstances, gluing the ring shut.  They then grew yeast carrying this engineered form. Next, they added a chemical called a ‘cross-linker’ to the cell, which ‘glues’ DNA to any nearby proteins – including any cohesin molecules.

Then the researchers split the yeast cells open, separated out the DNA-cohesin bundles from the yeast cells. Finally, they broke the cross-links between the DNA and cohesin, and found that the circular chromosomes were trapped inside the sealed cohesin ring.

If the ‘Blu-Tack model’ had been correct, then the yeast chromosomes would have been found as individual circles.  But the scientists found that the chromosomes were always paired together, proving they were linked by the sealed ring.

So this proves that the ring model is correct!

Here’s a little picture to explain what they found – the yeast chromosomes are in orange, while the sealed cohesin ring is blue.

Simple yet difficult
Although it sounds like a very simple idea, it took several years to get the experiments to work. So far, the ring model has only been proved in yeast, but it is highly likely that it will hold true for more complex organisms – including humans – because cohesin proteins are similar in most living things.

The paper describing these results was published in the journal Nature, one of the leading scientific publications in the world, and is a major breakthrough in the field of chromosome research.  Professor Nasmyth describes it as, “a fundamental piece of understanding of chromosome biology.”

This means that scientists around the world can now move forward with studies of cohesin and its mechanism – and find ways of targeting it to treat cancer.  The next step is to discover how the chromosomes get in and out of the ring. This is something that Professor Nasmyth and his team will be working on.

It may not lead to a new cancer treatment tomorrow, or even in the next five years, but this simple molecular ring trick has opened the door to a new world for chromosome researchers to explore.

You can hear Professor Nasmyth talking about cohesin and his research in this podcast from the 2008 NCRI Cancer Conference.

Kat