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Professor Mark Sansom, Head of Department
Trypanosomes yield their secrets in new study on chromosome segregation
Diagram showing the kinetochore complex (green) providing a bridge between the spindle microtubules (red) and the chromosomes (blue)
Trypanosomes appear to use a completely novel set of proteins to ensure the correct separation of their chromosomes during cell division.
This is the finding of research from Dr Bungo Akiyoshi, a Sir Henry Dale Fellow in the department, together with Professor Keith Gull in the Sir William Dunn School of Pathology.
Their work is described in a recent paper in Cell (1). It opens up new opportunities for the development of drugs against these organisms which cause tropical diseases, and provides insight into the enigmatic history of the earliest eukaryotes.
As a postdoc in Professor Gull’s lab, Dr Akiyoshi took the opportunity to continue his work on the kinetochore, a protein complex which links the chromosomes to the mitotic spindle ensuring that the chromosomes segregate correctly. But he shifted his research away from yeast to the trypanosome kinetochore.
‘Kinetochore components had been identified in various eukaryotes and it was assumed that all eukaryotes utilise common components for building kinetochores,’ he explains. ‘But no kinetochore protein was identifiable in kinetoplastids [to which trypanosomes belong]. Although people wanted to find out more, no-one could work on the kinetochores in these organisms because they couldn't identify components based on bioinformatics analysis.’
Dr Akiyoshi decided to tackle the problem using a different approach. He screened for genes that are up-regulated during mitosis and was lucky enough to identify a protein that he suspected was a kinetochore protein. This key finding led to a flurry of further discoveries.
‘I was thinking of investing up to two years in identifying one protein but I was very lucky – I found one within a year,’ he says. ‘Once I’d done this, I could identify others by affinity purification and mass spectrometry of the co-purifying proteins. Within 6 months or so, I found a further 18 proteins in total.’
Using inducible RNAi knockdown on a number of these proteins, he showed that they are essential for chromosome segregation and cell growth.
Sequence analysis of the proteins, named KKT proteins, revealed why they had not been picked up before. ‘They look completely different from conventional kinetochore proteins found in other eukaryotes,’ explains Dr Akiyoshi.
Although the trypanosome kinetochore serves the same function as all other kinetochores, bridging between DNA and the microtubules of the mitotic spindle, the components appear to be completely different.