title: Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity.
abstract: Subtelomeres consist of sequences adjacent to telomeres and contain genes involved in important cellular functions, as subtelomere instability is associated with several human diseases. Balancing between subtelomere stability and plasticity is particularly important for Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis. T. brucei regularly switches its major variant surface antigen, variant surface glycoprotein (VSG), to evade the host immune response, and VSGs are expressed exclusively from subtelomeres in a strictly monoallelic fashion. Telomere proteins are important for protecting chromosome ends from illegitimate DNA processes. However, whether they contribute to subtelomere integrity and stability has not been well studied. We have identified a novel T. brucei telomere protein, T. brucei TRF-Interacting Factor 2 (TbTIF2), as a functional homolog of mammalian TIN2. A transient depletion of TbTIF2 led to an elevated VSG switching frequency and an increased amount of DNA double-strand breaks (DSBs) in both active and silent subtelomeric bloodstream form expression sites (BESs). Therefore, TbTIF2 plays an important role in VSG switching regulation and is important for subtelomere integrity and stability. TbTIF2 depletion increased the association of TbRAD51 with the telomeric and subtelomeric chromatin, and TbRAD51 deletion further increased subtelomeric DSBs in TbTIF2-depleted cells, suggesting that TbRAD51-mediated DSB repair is the underlying mechanism of subsequent VSG switching. Surprisingly, significantly more TbRAD51 associated with the active BES than with the silent BESs upon TbTIF2 depletion, and TbRAD51 deletion induced much more DSBs in the active BES than in the silent BESs in TbTIF2-depleted cells, suggesting that TbRAD51 preferentially repairs DSBs in the active BES.
authors.affiliation: Department of Biological, Geological, and Environmental Sciences, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Sanaa E
authors.initials: SE
authors.lastname: Jehi
authors.affiliation: Department of Biological, Geological, and Environmental Sciences, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Wu
authors.affiliation: 1] Department of Biological, Geological, and Environmental Sciences, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA [2] The Rockefeller University, New York, NY 10065, USA [3] Department of Molecular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA [4] Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Bibo
authors.initials: B
authors.lastname: Li
mesh_terms: D053903:DNA Breaks, Double-Stranded; D015800:Protozoan Proteins / Q000502:physiology*; D051135:Rad51 Recombinase / Q000378:metabolism; D016615:Telomere; D059505:Telomere Homeostasis / Q000502:physiology*; D035341:Telomeric Repeat Binding Protein 2 / Q000502:physiology*; D014346:Trypanosoma brucei brucei / Q000235:genetics*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015800:Protozoan Proteins; C000595357:TRF-interacting factor 2, Trypanosoma brucei; D035341:Telomeric Repeat Binding Protein 2; D014643:Variant Surface Glycoproteins, Trypanosoma; D051135:Rad51 Recombinase