Faking it: Researchers create artificial chromosome to explore cell division machinery

15 April 2008

Scientists from Edinburgh have created an artificial chromosome that gives them insight into cell division and could potentially help in the hunt for new cancer therapies and new ways to produce stem cells.

When cells divide, it’s essential that the chromosomes are shared out correctly. For a cell, having too many or too few copies of a particular chromosome can have serious consequences. In eggs or sperm, gain or loss of chromosomes can cause miscarriage or birth defects, including Down’s syndrome. In somatic cells (i.e. all other body cells), it can cause cancer.

Professor William C Earnshaw from the University of Edinburgh led a team of colleagues and researchers from the National Institutes of Health, USA and the University of Nagoya, Japan to produce an artificial chromosome they could use to study how a key part of the cell division machinery - the centromere - works.

The centromere is a length of DNA essential for proper chromosome segregation. It is a bit like a belt, found at the ‘waist’ of two identical copies of a chromosome when they’re ready to divide. Protein complexes assemble on the centromere and attach to the fibres that pull apart the chromosomes, one into each daughter cell.

Researchers know that human centromeres have distinctive, repetitive DNA sequences present. However, they also know that the presence of these sequences is not enough to make a length of DNA act like a centromere, and sometimes centromeres can appear elsewhere on a chromosome. These findings suggest that changes to genes that aren’t to do with the actual DNA sequence are involved in centromere function. These ‘epigenetic’ changes could include physical modifications to the DNA or the proteins it wraps around to form chromosomes.

Previously, scientists were unable to study and manipulate single centromeres to investigate their structure and function without killing the cell. Now though, Professor Earnshaw and colleagues have created an artificial chromosome containing a synthetic centromere and introduced it into cells. The cell does not need this chromosome to live, which means that researchers are free to manipulate the synthetic centromere (including epigenetic factors involved) to study how it works, without damaging the cell.

This work should help increase our understanding of how chromosome segregation can go wrong in the body. With this information, researchers could potentially develop ways to stop these mistakes from happening in normal cells, but encourage them in cancer cells, to trigger cell death.

Ultimately, the artificial chromosome developed as part of this work could be used as a vector to carry genes into a cell. One potential application of this would be to trigger reprogramming in cells - a process that can convert mature cells back to stem cells, potentially helping damaged or diseased tissue regenerate.

Currently, the genes used reprogramming can cause stem cells to become cancerous. The advantage of using the artificial chromosome is that once reprogramming has occurred the centromere could be ‘switched off’ in the cell, removing the potentially hazardous genes from the cell.

Image: Photo showing human chromosomes (blue) from a dividing cell with the human artificial chromosome (green) present; WC Earnshaw

References

Nakano M et al. Inactivation of a human kinetochore by specific targeting of chromatin modifiers. Dev Cell 2008 [in press]