Trypanosoma brucei BRCA2 acts in antigenic variation and has undergone a recent expansion in BRC repeat number that is important during homologous recombination.
Antigenic variation in Trypanosoma brucei has selected for the evolution of a massive archive of silent Variant Surface Glycoprotein (VSG) genes, which are activated by recombination into specialized expression sites. Such VSG switching can occur at rates substantially higher than background mutation and is dependent on homologous recombination, a core DNA repair reaction. A key regulator of homologous recombination is BRCA2, a protein that binds RAD51, the enzyme responsible for DNA strand exchange. Here, we show that T. brucei BRCA2 has undergone a recent, striking expansion in the number of BRC repeats, a sequence element that mediates interaction with RAD51. T. brucei BRCA2 mutants are shown to be significantly impaired in antigenic variation and display genome instability. By generating BRCA2 variants with reduced BRC repeat numbers, we show that the BRC expansion is crucial in determining the efficiency of T. brucei homologous recombination and RAD51 localization. Remarkably, however, this appears not to be a major determinant of the activation of at least some VSG genes.
Hartley
Claire L
CL
The Wellcome Centre for Molecular Parasitology and Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow Biomedical Research Centre, 120 University Place, Glasgow G12 8TA, UK.
McCulloch
Richard
R
D000818:Animals; D000940:Antigenic Variation / Q000235:genetics*; D024682:BRCA2 Protein; D042622:DNA Repeat Expansion; D016054:DNA, Protozoan / Q000737:chemistry* / Q000235:genetics; D024522:Genes, BRCA2; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology; D051135:Rad51 Recombinase / Q000235:genetics* / Q000502:physiology; D011995:Recombination, Genetic; D020449:Repetitive Sequences, Amino Acid; D014346:Trypanosoma brucei brucei / Q000235:genetics* / Q000276:immunology*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000235:genetics*
D024682:BRCA2 Protein; D016054:DNA, Protozoan; D015800:Protozoan Proteins; D014643:Variant Surface Glycoproteins, Trypanosoma; D051135:Rad51 Recombinase