Active Genetics & Molecular Biology Cells, Biochemistry & Physiology

Understanding the mechanism of chromosome segregation in the kinetoplastid parasite Trypanosoma brucei

Funder Wellcome Charity-funded
Recipient organisation University of Edinburgh
Funding £3.6M
Period Jan 2024 — Dec 2031

In plain English

AI plain-English summary

Nearly a billion people are at risk of diseases caused by kinetoplastid parasites, and researchers have discovered that these parasites use a completely different set of proteins to pull their chromosomes apart during cell division. This matters because the parasites that cause sleeping sickness, Chagas disease, and leishmaniasis rely on this unusual machinery to multiply inside their human hosts. For 40 years, scientists assumed that the protein complex that separates chromosomes—the kinetochore—was built from similar parts across all complex cells. But in *Trypanosoma brucei*, the kinetochore is made of 25 unique proteins found nowhere else in nature. This fundamental difference means drugs that disrupt these parasite-specific proteins could kill the pathogen without harming human cells. If this research succeeds, it will reveal exactly how these unconventional kinetochores are organised and controlled. The immediate impact is fundamental: a deeper understanding of how evolution can solve the same biological problem in radically different ways. The practical payoff—new drug targets for neglected tropical diseases—will depend on future work, but the discovery of a completely alternative chromosome segregation system opens a door that simply did not exist before.

View original technical description
Nearly a billion people are at risk of infectious diseases caused by kinetoplastid parasites. Kinetoplastids are a group of eukaryotes that are evolutionarily highly divergent from commonly studied eukaryotes. Our overall objective is to reveal how unconventional machinery and regulatory networks drive proliferation of kinetoplastid parasites using Trypanosoma brucei as a model. Centromeres and their associated intricate kinetochore machinery (~60 proteins) are essential for mediating accurate chromosome segregation in all eukaryotes. Since the identification of the first kinetochore proteins ~40 years ago, it appeared that kinetochore structure and their regulation would be broadly similar across all eukaryotes. It was therefore surprising when we discovered that kinetochores in Trypanosoma brucei are composed of unique proteins, KKT1-to-KKT25. These highly divergent kinetochores provide an attractive drug target for combating kinetoplastid diseases. Our goal is to understand how the unique components and underlying centromeres are organized to carry out conserved kinetochore functions. We will also dissect the nature of noncanonical cell cycle control executed by conserved mitotic regulators. Identification of novel mechanisms will not only provide opportunities for drug development against kinetoplastid parasites but also deepen our understanding of intricate chromosome segregation machinery in all eukaryotes.

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Researchers

Bungo Akiyoshi (EPMC Awardee)

Related Research

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Elucidating the mechanism of chromosome segregation in Trypanosoma brucei.
Chromosome segregation machinery in a basal eukaryotic system
Chromatin associated proteins and histone post-translational modification dynamics in the development and immune evasion of the sleeping sickness para
Discovering the mechanism of how trypanosomes epigenetically assemble unconventional kinetochores at centromeres
Deciphering mechanisms of epigenetic regulation in Trypanosoma brucei, an evolutionarily distinct human pathogen.

Original classification

Discovery Award

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