Telomere structure and function in Trypanosoma brucei

Summary

Principal Investigator: GEORGE CROSS
Abstract: DESCRIPTION: (provided by the applicant): The objective of this proposal is to study telomere structure and function in Trypanosoma brucei and to explore the potential of T. brucei as a model system, to contribute to the understanding of telomere structure, synthesis and regulation in mammalian cells. The specific aims are (1) to identify and characterize proteins that interact with telomeric repeats in T. brucei and (2) to characterize the telomerase complex of T. brucei. African trypanosomiasis has two major manifestations: the human disease known as Sleeping Sickness and the animal disease Nagana (meaning loss of spirits in the Zulu language). Trypanosomiasis is endemic in equatorial Africa, where it is transmitted, among humans and animals, by Glossina, the Tsetse. The native African fauna are almost universally infected, providing a vast reservoir of potential human pathogens. Focal human epidemics are a serious reality and an increasing threat. If untreated, trypanosomiasis is rapidly fatal, and probably kills around 100,000 people annually. The available treatments are unsatisfactory and often ineffective. One of the major reasons for the persistence of African trypanosomes is their unique and efficient mechanism to evade the mammalian immune response. In a process known as Antigenic Variation, the majority of the trypanosome population is destroyed by the immune responses to a variant surface glycoprotein (VSG) coat, but individual trypanosomes switch their VSG, using a repertoire of hundreds of VSG genes, evade destruction, and seed successive waves of parasitemia. To be expressed, a VSG gene has to be located at a telomeric 'expression site'. Although antigenic variation has drawn attention to trypanosome telomeres, there has been almost no research targeted specifically to understanding trypanosome telomere structure and maintenance. Mammalian telomeres have attracted much attention, because of their central role in cell senescence and cancer. As most somatic mammalian cells replicate, their telomeres shorten, placing a limit on the number of times a cell can divide. Overcoming this restriction, by reactivating telomerase, is a necessary step among the many genetic changes that lead to cancer. Because of this, drugs that target telomerase are being sought for the treatment of cancer. Such drugs could also be valuable in the treatment of trypanosomiasis. There are significant similarities between the telomeres of trypanosomes and humans, so trypanosomes would be a useful model in which to study events that are relevant to human aging and cancer.
Funding Period: 2002-02-01 - 2006-01-31
more information: NIH RePORT

Top Publications

  1. pmc Trypanosome telomeres are protected by a homologue of mammalian TRF2
    Bibo Li
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
    Mol Cell Biol 25:5011-21. 2005
  2. ncbi Unusual histone modifications in Trypanosoma brucei
    Christian J Janzen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
    FEBS Lett 580:2306-10. 2006
  3. pmc Expression site silencing and life-cycle progression appear normal in Argonaute1-deficient Trypanosoma brucei
    Christian J Janzen
    Laboratory of Molecular Parasitology, The Rockefeller University, Box 185, 1230 York Avenue, New York, NY 10021 6399, USA
    Mol Biochem Parasitol 149:102-7. 2006
  4. pmc Telomerase-independent stabilization of short telomeres in Trypanosoma brucei
    Oliver Dreesen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
    Mol Cell Biol 26:4911-9. 2006
  5. ncbi Selective di- or trimethylation of histone H3 lysine 76 by two DOT1 homologs is important for cell cycle regulation in Trypanosoma brucei
    Christian J Janzen
    Laboratory of Molecular Parasitology, The Rockefeller University, New York, New York 10021, USA
    Mol Cell 23:497-507. 2006
  6. pmc Consequences of telomere shortening at an active VSG expression site in telomerase-deficient Trypanosoma brucei
    Oliver Dreesen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021 6307, USA
    Eukaryot Cell 5:2114-9. 2006
  7. pmc Telomere length in Trypanosoma brucei
    Oliver Dreesen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021 6399, USA
    Exp Parasitol 118:103-10. 2008
  8. pmc RAP1 is essential for silencing telomeric variant surface glycoprotein genes in Trypanosoma brucei
    Xiaofeng Yang
    Department of Biological, Geological, and Environmental Sciences, Center for Gene Regulation in Health and Diseases, Cleveland State University, Cleveland, OH 44115, USA
    Cell 137:99-109. 2009

Detail Information

Publications8

  1. pmc Trypanosome telomeres are protected by a homologue of mammalian TRF2
    Bibo Li
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
    Mol Cell Biol 25:5011-21. 2005
    ..This work also establishes T. brucei as an attractive model for telomere biology...
  2. ncbi Unusual histone modifications in Trypanosoma brucei
    Christian J Janzen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
    FEBS Lett 580:2306-10. 2006
    ..Possible functions and evolutionary explanations for these unusual histone modifications are discussed...
  3. pmc Expression site silencing and life-cycle progression appear normal in Argonaute1-deficient Trypanosoma brucei
    Christian J Janzen
    Laboratory of Molecular Parasitology, The Rockefeller University, Box 185, 1230 York Avenue, New York, NY 10021 6399, USA
    Mol Biochem Parasitol 149:102-7. 2006
  4. pmc Telomerase-independent stabilization of short telomeres in Trypanosoma brucei
    Oliver Dreesen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
    Mol Cell Biol 26:4911-9. 2006
    ..brucei is not regulated by a protein-counting mechanism. Many minichromosomes were lost after long-term culture in the absence of telomerase, which may reflect their different mitotic segregation properties...
  5. ncbi Selective di- or trimethylation of histone H3 lysine 76 by two DOT1 homologs is important for cell cycle regulation in Trypanosoma brucei
    Christian J Janzen
    Laboratory of Molecular Parasitology, The Rockefeller University, New York, New York 10021, USA
    Mol Cell 23:497-507. 2006
    ..We propose that DOT1A and DOT1B influence the trypanosome cell cycle by regulating the degree of H3K76 methylation...
  6. pmc Consequences of telomere shortening at an active VSG expression site in telomerase-deficient Trypanosoma brucei
    Oliver Dreesen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021 6307, USA
    Eukaryot Cell 5:2114-9. 2006
    ..We propose a model in which subtelomeric-break-induced replication-mediated repair at a short ES telomere leads to duplicative gene conversion and expression of a new VSG...
  7. pmc Telomere length in Trypanosoma brucei
    Oliver Dreesen
    Laboratory of Molecular Parasitology, The Rockefeller University, 1230 York Avenue, New York, NY 10021 6399, USA
    Exp Parasitol 118:103-10. 2008
    ..brucei have shorter telomeres than extensively propagated Lister 427 clones, suggesting a link between laboratory adaptation, telomere growth, and VSG switching rates...
  8. pmc RAP1 is essential for silencing telomeric variant surface glycoprotein genes in Trypanosoma brucei
    Xiaofeng Yang
    Department of Biological, Geological, and Environmental Sciences, Center for Gene Regulation in Health and Diseases, Cleveland State University, Cleveland, OH 44115, USA
    Cell 137:99-109. 2009
    ..This graduated silencing pattern suggests that telomere integrity plays a key role in tbRAP1-dependent silencing and VSG regulation...