Publication Date:
2009-04-17
Description:
Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of the causes of nagana in cattle. This protozoan parasite evades the host immune system by antigenic variation, a periodic switching of its variant surface glycoprotein (VSG) coat. VSG switching is spontaneous and occurs at a rate of about 10(-2)-10(-3) per population doubling in recent isolates from nature, but at a markedly reduced rate (10(-5)-10(-6)) in laboratory-adapted strains. VSG switching is thought to occur predominantly through gene conversion, a form of homologous recombination initiated by a DNA lesion that is used by other pathogens (for example, Candida albicans, Borrelia sp. and Neisseria gonorrhoeae) to generate surface protein diversity, and by B lymphocytes of the vertebrate immune system to generate antibody diversity. Very little is known about the molecular mechanism of VSG switching in T. brucei. Here we demonstrate that the introduction of a DNA double-stranded break (DSB) adjacent to the approximately 70-base-pair (bp) repeats upstream of the transcribed VSG gene increases switching in vitro approximately 250-fold, producing switched clones with a frequency and features similar to those generated early in an infection. We were also able to detect spontaneous DSBs within the 70-bp repeats upstream of the actively transcribed VSG gene, indicating that a DSB is a natural intermediate of VSG gene conversion and that VSG switching is the result of the resolution of this DSB by break-induced replication.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688456/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688456/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boothroyd, Catharine E -- Dreesen, Oliver -- Leonova, Tatyana -- Ly, K Ina -- Figueiredo, Luisa M -- Cross, George A M -- Papavasiliou, F Nina -- R01 AI021729/AI/NIAID NIH HHS/ -- R01 AI021729-25/AI/NIAID NIH HHS/ -- R01 AI085973/AI/NIAID NIH HHS/ -- R01AI021729/AI/NIAID NIH HHS/ -- England -- Nature. 2009 May 14;459(7244):278-81. doi: 10.1038/nature07982. Epub 2009 Apr 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Lymphocyte Biology, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19369939" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigenic Variation/*genetics
;
*DNA Breaks, Double-Stranded
;
DNA Repair/genetics
;
DNA Replication
;
Deoxyribonucleases, Type II Site-Specific/genetics/*metabolism
;
Gene Conversion/genetics
;
*Models, Genetic
;
Polymerase Chain Reaction
;
Saccharomyces cerevisiae/enzymology/genetics
;
Saccharomyces cerevisiae Proteins/genetics/*metabolism
;
Sequence Analysis
;
Trypanosoma brucei brucei/*genetics/*immunology
;
Variant Surface Glycoproteins, Trypanosoma/genetics/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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