In each of our cells, most of the genetic material is packaged safely within the nucleus, which is protected by a double membrane. The biochemistry behind how this membrane transforms when cells divide has finally been unravelled, offering insights that could provide new ways of fighting cancer and some rare genetic disorders.
During cell division, the membrane that surrounds the nucleus breaks down and reforms in the two daughter cells. Researchers have been split on the precise mechanisms that govern membrane reformation. One view is that proteins alone control the membrane's transformations. Another possibility is that changes in lipids – a vast group of fat-related compounds – are responsible.
Experiments had failed to show which of these two ideas was right, because it was difficult to alter lipid levels in specific compartments of cells without affecting other cellular processes.
Banafshe Larijani at Cancer Research UK's London Research Institute and her colleagues have now overcome that hurdle. They came up with a technique that transforms a type of lipid called a diacylglycerol (DAG) into another lipid, within the nuclear membrane.
Chemical cascade
The technique involves inserting two fragments of DNA into the nucleus of a cell. This causes the cell to make two proteins: the first attaches itself to the nuclear membrane, the second floats around the cell. Adding a drug – rapalogue – to the mix causes the second protein to stick to the first, which in turn causes a chemical cascade that transforms the DAG into a different kind of lipid.
Crucially, they targeted a form of DAG that does not bind to proteins, so converting it into a different lipid does not affect any processes involving proteins in the cell.
The team tested the effect of this lipid manipulation on cell division in monkey and human cancer cells. The lower the level of DAG present in the nuclear membrane, the greater the membrane malformation and chance of cell death.
This demonstrates that lipids play a role in nuclear membrane reformation that does not depend on proteins.
Larijani says it "opens the door to finding ways to kill cancerous cells" by focusing on lipids that are important to the nuclear membrane's development.
Sausage pieces
As the nucleus divides, sausage-shaped fragments of its membrane float around the cell. The fragments have curved ends, and Larijani says that changes in lipid composition generate these curves, without which the fragments cannot reassemble correctly into new membranes.
More than a dozen rare genetic conditions such as Hutchinson-Gilford progeria syndrome, which is characterised by premature ageing in children, have been linked to irregularities in cell division. A better understanding of the way the nuclear membrane forms when cells divide could be key to treating these disorders.
The research also offers a new focus for preventing the irregular cell division that underlies many cancers.
"As a result of this work we now know with confidence that DAG plays a structural role in membrane dynamics," says Vytas Bankaitis, at the Texas A&M Health Science Center in College Station, who was not involved in the study. "If we could find a molecule with suitable characteristics, this manipulation could be done [in humans], which is something that has not really been considered before."
Journal reference: PLoS ONE DOI: 10.1371/journal.pone.0051150
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