Chromosomes, microtubules and proteins in a cellular jam session

Cell and Developmental Biology

Researchers from the CRG reveal the mechanism by which chromosomes orchestrate cell division

Maceo Parker is, without doubt, one of the greats in the history of jazz. Who would not want to go a concert by this saxophonist? Undoubtedly, it would be a fascinating experience. And it is likely that Parker would be accompanied by a small band of musicians. Maybe a trumpet, a piano, a drum kit, perhaps a double bass.

Together they would start to play a tune, following the score. Then, at a given point, they would start to improvise. Each musician would not play just anything, instead they all move within the same scale but without following a specific notation. Maybe Parker would be the first person to depart from the score and later he would be joined by the rest of the musicians.

However much they improvised, the result would sound really good. Whilst the musicians are not tied to any specific music, they are trained in jazz and they know what to do so that it makes sense, although they do not know exactly how it will come out.

Interestingly, the cells of our body work in a similar way. At least when they divide. And that happens very often. In fact, as you are reading this article, many thousands of cells in your body are duplicating and splitting into two. As you read. In this way the skin is regenerated almost every day, lost hair is replenished and tissue damage is repaired. Like improvisation in jazz, the components of the cell also lack a score with specific instructions. Even so, they intuit and carry out actions that, in the end, contribute to the proper functioning of the cell.

Isabelle Vernos is an ICREA Research Professor and leader of the Microtubule Function and Cell Division group at the Centre for Genomic Regulation (CRG). She has spent decades researching the mechanism of cell division which, ultimately, is the basis of life. Because life starts like this: with a fertilized egg that begins to divide thousands and thousands of times to end up forming a human being.

And although it may perhaps seem a trivial process, it is a very complex mechanism that has to work well each and every time it takes place. If not, it could be that the organism does not develop, for example; or that it generates defects, such as Down’s syndrome, a genetic disorder in which the chromosomes have not been separated, divided and distributed correctly.

“We want to understand how that division takes place, what makes the cell move from a state of quiescence to division and differentiation, forming a tissue or an embryo.” We try to understand how the cell builds a tiny molecular machine with which it manages its chromosomes, duplicates them, organises and divides them properly”, explains Vernos passionately.


A harness called the mitotic spindle

When the cell begins the process of division, it duplicates its chromosomes, small, stick-shaped bodies that store genetic material. These chromosomes and their copies form a sort of tangle, like a ball of wool, and the cell must organise them and place one copy of each chromosome on each side, in order to be able to divide.

To do this, the filament-shaped elements known as microtublules are essential. They form a sort of harness which can be put up and taken down, arranged and rearranged, put in one position or another. These structures are responsible for forming a kind of rugby ball-shaped mesh around the chromosomes, anchoring itself to them to help them separate correctly and then pulling them hard when the cell splits into two to ensure that each new cell has the same chromosomal content.

It is a fairly intelligent system, capable of detecting errors and trying to fix them. Because in the event that these harnesses realise they are not well anchored to the chromosome, for example, they release the hooks in order to reset them.

“Better understanding how this mechanism works is the key to being able to find answers to problems such as tumour proliferation”, points out the CRG group leader, Isabelle Vernos. “Applied science can only be fed from basic science. And understanding how the cell works, how a process functions, the mechanisms and the proteins involved, is how you get ideas to apply in pathological situations”.

And in the case of cancer, for example, where there is a large proliferation of cells, these do not only divide without control but they also do it wrongly, leading to a great diversity and hindering the treatment of tumours. Interestingly, one of the first methods that was used to combat oncogenesis was a compound that interferes with the formation of microtubules, because if these cannot be formed, the cell cannot divide and the tumour proliferation system is brought to a halt. However, those drugs had a serious side effect: they also prevented cell division in healthy tissues, something which was not very beneficial to the patient.


A chain of command

Vernos and her team of researchers focus on the study of a very specific mechanism that occurs when the cell enters mitosis, i.e., when it starts to divide. Surprisingly, it is the chromosomes themselves that direct the process that ends up in them being separated. And Vernos and her team have discovered the mechanism which orchestrates the action. They have published the results of their study in the journal Current Biology .

This mechanism involves a kinase [a type of enzyme with the ability to modify other molecules] known as Aurora A which they have discovered controls a protein, NEDD1, responsible for marking the exact spot where the microtubules are going to form.

“The chromosome, which to a certain extent organises this process, activates this kinase Aurora A that in turn tells the NEDD1 protein to form microtubules next to the chromosomes. Forming near the chromosome makes it easier to establish the appropriate interactions for ending up with the same chromosomal content in the two new cells”, explains Isabelle.

In some way, a kind of chain of command is set up, where the chromosomes give orders to Aurora A to activate to NEDD1 to form the microtubules. The chromosomes control more or less where this is going to happen and this helps them organise themselves properly. Just like jazz musicians, they know what scale they have to play in and this helps them produce pleasing melodies, despite not having a specific score.

Reference work:

Pinyol R, Scrofani J, Vernos I.
“The role of NEDD1 phosphorylation by Aurora A in chromosomal microtubule nucleation and spindle function.”
Curr Biol, 23(2):143-9 (2013).