CNIO dives into key cell division process that opens doors to disease treatment – Society

Researchers from the Center for Genomic Regulation (CRG), the National Cancer Research Center (CNIO) and the Supreme Council of Scientific Research (IBMB-CSIC) have achieved the equivalent of making a film that shows how human cells begin to form their cells. microtubules that lay the foundation for future advances in the treatment of diseases ranging from cancer to neurodevelopmental disorders.

The researchers of the study, published in the journal Science, explain that cells are constantly dividing. With each division, the genetic information contained in the chromosomes is duplicated, and each daughter cell receives a complete copy of the genetic material.

This is a complex process that involves subtle and rapid changes within the cell. To make this possible, the cell contains microtubules – tiny tube-like structures. This study helps to understand how they are formed.

Microtubules not only play a key role in cell division, but also act as highways for transporting cellular components between different regions of the cell. They are also structural elements that, among other things, give shape to the cell itself. A good understanding of their preparation has implications for many areas of biomedicine.

MOLECULAR RING TRIGGERING MICROTUBE FORMATION

The now-obtained high-resolution images answer a question that has been floating around for many years: how microtubule formation begins in the early stages of cell division.

We now know that it all starts by closing itself to form a ring, a complex structure made up of several proteins called a gTuRC.

New work by CRG and CNIO reveals the mechanism by which gTuRC locks into a ring and effectively becomes the perfect template to drive microtubule formation. Closing of gTuRC occurs upon attachment of the first molecular fragment of a microtubule.

Visualizing this process required purifying gTuRC from human cells and reproducing the microtubule initiation process in vitro. The samples were observed using cryo-electron microscopes, and artificial intelligence was used to analyze the data.

ONE MILLION SHOTS FROM THE ATOMIC SCALE FILM

One of the problems was the high speed of the microtubule building process. The CRG group was able to slow it down in the laboratory and also stop the growth of microtubules so that they could analyze the initial stages of the process.

Microtubules under construction were observed on the IBMB-CSIC electron cryomicroscopy platform located at the Joint Electron Microscopy Center (JEMCA) at the ALBA synchrotron.

In practice, having more than a million microtubules in different growth phases is equivalent to having many high-resolution movie frames. You just need to position them correctly to see the movie. This work fell to the CNIO team, which used artificial intelligence techniques to complete it.

HEALTH CONSEQUENCES

As Oscar Lorca, director of the CNIO’s structural biology program and the paper’s main co-author, explained, “This discovery is relevant because it affects a very simple mechanism of cell division that was not known to occur in humans.” “

This is useful background knowledge for learning how to correct errors in microtubule function that have been linked to cancer, neurodevelopmental disorders, and other conditions ranging from respiratory problems to heart disease.

“Some drugs used today to treat cancer prevent the formation or dynamics of microtubules,” says Llorca. “However, these drugs indiscriminately target microtubules in both cancer and healthy cells, leading to side effects. “Detailed knowledge of how microtubules form could help develop more targeted treatments that affect microtubule formation and lead to advances in the treatment of cancer and other diseases,” he said.

NEXT STEP: UNDERSTAND THE RULES

For his part, co-author Thomas Surrey explained the next steps in understanding microtubules, which involve understanding how their formation is regulated.

“The nucleation process decides where and how many microtubules are in the cell. It is likely that the conformational changes we observe are controlled by regulators that have not yet been discovered in cells. Several candidates have been described in other studies, but their mechanism of action is unclear,” he explained.

Future work could change the understanding of how microtubules function and, over time, “provide alternative sites that can be targeted to prevent cancer cells from continuing the cell cycle,” Surrey concludes.

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