Evolutionary cell biology of chromosome segregation
Faithful transmission of genetic material is essential for the survival of all organisms. Defects in this process lead to cancer or birth defects in humans. Elucidating the mechanism of chromosome segregation is therefore key to understanding the molecular basis of these diseases. Eukaryotic chromosome segregation is driven by the kinetochore that assembles onto centromeric DNA to capture spindle microtubules and govern the movement of chromosomes. Its molecular mechanism has been revealed from studies of conventional model eukaryotes, such as yeasts, worms, flies and human. However, these organisms are closely related in the evolutionary timescale and it therefore remains unclear whether all eukaryotes utilize a similar mechanism. The evolutionary origins of the segregation apparatus also remain enigmatic.
To obtain insights into these questions, my group is studying Trypanosoma brucei, an experimentally-tractable kinetoplastid parasite that branched early in eukaryotic history. No canonical kinetochore component has been identified and the design principle of kinetochores might be fundamentally different in kinetoplastids. Furthermore, these organisms do not appear to possess a functional spindle checkpoint that monitors kinetochore-microtubule attachments.
With these unique features and the long evolutionary distance from other eukaryotes, understanding the mechanism of chromosome segregation in T. brucei should reveal fundamental requirements for eukaryotic segregation machinery and may also provide hints about the origin and evolution of the segregation apparatus. By identifying relevant proteins and characterizing them in vivo and in vitro, my group is beginning to reveal the mechanism of chromosome segregation in T. brucei.
Etiologically, T. brucei causes African sleeping sickness, which is invariably lethal if untreated and is responsible for more than 10,000 deaths annually in sub-Saharan Africa. The current therapy is highly toxic and there is little prospect of vaccine development due to antigenic variation. Therefore, understanding the biology of trypanosomes is also medically important to facilitate drug design that specifically kills parasites. Furthermore, obtained insights in T. brucei should also lead to a better understanding of other related trypanosomatids that also cause devastating human diseases (e.g. Chagas disease caused by Trypanosoma cruzi and leishmaniasis caused by Leishmania species).
- Akiyoshi B and Gull K. (2013) Evolutionary cell biology of chromosome segregation: insights from trypanosomes. Open Biology 3: 130023
- Akiyoshi B, Nelson CR, Duggan N, Ceto S, Ranish JA, and Biggins S. (2013) The Mub1/Ubr2 ubiquitin ligase complex regulates the conserved Dsn1 kinetochore protein. PLoS Genetics 9(2): e1003216
- Gonen S, Akiyoshi B, Iadanza MG, Shi D, Duggan N, Biggins S and Gonen T. (2012) The structure of purified kinetochores reveals multiple microtubule attachment sites. Nature Structural and Molecular Biology 19: 925-929
- Akiyoshi B and Biggins S. (2012) Reconstituting the kinetochore-microtubule interface: what, why, and how. Chromosoma 121: 235-250
- Akiyoshi B, Sarangapani K, Powers AF, Nelson CR, Reichow SL, Arellano-Santoyo HS, Gonen T, Ranish JA, Asbury CL, and Biggins S. (2010) Tension directly stabilizes reconstituted kinetochore-microtubule attachments. Nature 468: 576-9
(A) Mitotic chromosome segregation.
(B) Cell division cycle of Trypanosoma brucei. Trypanosomes possess two DNA-containing organelles, kinetoplast (a structure in the mitochondrion that contains mitochondrial DNA) and nucleus, both of which must be segregated faithfully.