'Lasso' protein target for less toxic drugs

21 May 2008

Chromosome ‘lassoing’: New key mechanism in cell division provides target for less toxic drugs

Scientists have revealed the function of a protein that is indispensable for passing on an accurate copy of the genome from mother to daughter cells. The study, published in Cell, opens up new avenues of research to reduce the toxicity of chemotherapy in the treatment of cancer.

The researchers have compared the protein to a cowboy’s lasso as it catches chromosomes and ties them to a transitory structure assembled during cell division. Once they have been ‘tied up’, the chromosomes await the end of replication to be equally distributed between the two daughter cells.

If the ‘lasso’ protein doesn’t catch them, chromosomes end up being randomly scattered, with potentially disastrous genetic effects as cells that survive this receive the wrong genetic inheritance, with dire consequences.

The structure and function of this chromosomal lasso were discovered in Milan, at the European Institute of Oncology (IEO). “We’ve been studying a molecule called Ndc80”, explains Andrea Musacchio, principal author of the study, and head of a research group in the Department of Experimental Oncology. “This protein is a key player necessary for the correct distribution of genetic inheritance. Ndc80 could potentially be used as a target for new drugs that would have fewer toxic side-effects than current drugs, such as paclitaxel (originally called taxol), which mainly act as inhibitors of cell replication.”

Although many drugs used in traditional chemotherapy act on molecular targets that are in involved in the duplication of cells (during a phase known as ‘mitosis’), these targets also have other cellular functions. Ndc80, on the other hand, performs its job only during mitosis. By blocking Ndc80 only the dividing cells are affected.

Musacchio and his colleagues, together with co-author Peter De Wulf and his research team, are further testing a number of substances that might be able to block the action of Ndc80.