|Trypanosoma brucei Orc1 is essential for nuclear DNA replication and affects both VSG silencing and VSG switching.
|Year of Publication
|Benmerzouga I, Concepción-Acevedo J, Kim H-S, Vandoros AV, Cross GAM, Klingbeil MM, Li B
|Antigenic Variation, DNA Replication, DNA, Protozoan, Gene Silencing, Genes, Protozoan, Membrane Glycoproteins, Origin Recognition Complex, Promoter Regions, Genetic, Trypanosoma brucei brucei, Variant Surface Glycoproteins, Trypanosoma
Binding of the Origin Recognition Complex (ORC) to replication origins is essential for initiation of DNA replication, but ORC has non-essential functions outside of DNA replication, including in heterochromatic gene silencing and telomere maintenance. Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis, uses antigenic variation as a major virulence mechanism to evade the host's immune attack by expressing its major surface antigen, the Variant Surface Glycoprotein (VSG), in a monoallelic manner. An Orc1/Cdc6 homologue has been identified in T. brucei, but its role in DNA replication has not been directly confirmed and its potential involvement in VSG repression or switching has not been thoroughly investigated. In this study, we show that TbOrc1 is essential for nuclear DNA replication in mammalian-infectious bloodstream and tsetse procyclic forms (BF and PF). Depletion of TbOrc1 resulted in derepression of telomere-linked silent VSGs in both BF and PF, and increased VSG switching particularly through the in situ transcriptional switching mechanism. TbOrc1 associates with telomere repeats but appears to do so independently of two known T. brucei telomere proteins, TbRAP1 and TbTRF. We conclude that TbOrc1 has conserved functions in DNA replication and is also required to control telomere-linked VSG expression and VSG switching.
|PubMed Central ID
|R01 AI021729 / AI / NIAID NIH HHS / United States
R01 AI066095 / AI / NIAID NIH HHS / United States
R01AI021729 / AI / NIAID NIH HHS / United States
R01AI066095 / AI / NIAID NIH HHS / United States
R21 AI085366 / AI / NIAID NIH HHS / United States
R21AI85366 / AI / NIAID NIH HHS / United States