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Mechanism of cell cycle regulation molecules revealed

The new research shows how a large molecule known as the anaphase-promoting complex/cyclosome (APC/C) regulates cell division by marking proteins within cells for destruction.

Cancer is a disease of cell proliferation, which occurs through the biological process known as the cell cycle. A series of checks and controls regulate each stage of this complex process, but in cancer these 'brakes' become faulty.

The APC/C is one of those cell cycle controls. By marking a set of proteins for destruction, it releases the brakes and allows cell division to proceed.

Until recently nobody was quite sure how the APC/C worked at the molecular level, but a team of scientists at the Institute of Cancer Research (ICR) have now uncovered how this molecular targeting system works.

Study leader Professor David Barford FRS, Professor of Molecular Biology at the ICR, said: "We have described how proteins marked for destruction are recognised by cell cycle regulatory systems. We hope that this information will allow us to begin developing therapies that control APC/C activity in cancer."

APC/C marks proteins for destruction by 'tagging' them with a small protein label called 'ubiquitin'. These tags are recognised by molecular machines known as proteasomes, which are then responsible for breaking down the marked proteins.

The role of the APC/C is to ensure that the correct proteins are destroyed at the right time in the cell cycle, and it does this by ‘ubiquitinating' proteins — marking them with ubiquitin. But how do APC/Cs know which proteins to mark?

"Proteins contain regions known as 'degrons', destruction boxes (D boxes) and KEN boxes," explains Professor Barford. "The APC/C can then bind to these degrons using adaptors known as 'coactivators', enabling ubiquitination of the proteins."

The group's recent work shows the molecular structure of a D box bound to a coactivator, revealing how these coactivators actually recognise degrons.

"Being able to show how D boxes are identified on a molecular level has yielded powerful insights into the processes which regulate the cell cycle," Professor Barford concludes. "This could ultimately help us to understand the role of APC/C coactivators in tumour development and to design new drugs which target this mechanism."

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