Telomere Length Affects the Frequency and Mechanism of Antigenic Variation in

English version České info

Trypanosoma brucei is a master of antigenic variation and immune response evasion. Utilizing a genomic repertoire of more than 1000 Variant Surface Glycoprotein-encoding genes (VSGs), T. brucei can change its protein coat by “switching” from the expression of one VSG to another. Each active VSG is monoallelically expressed from only one of approximately 15 subtelomeric sites. Switching VSG expression occurs by three predominant mechanisms, arguably the most significant of which is the non-reciprocal exchange of VSG containing DNA by duplicative gene conversion (GC). How T. brucei orchestrates its complex switching mechanisms remains to be elucidated. Recent work has demonstrated that an exogenous DNA break in the active site could initiate a GC based switch, yet the source of the switch-initiating DNA lesion under natural conditions is still unknown. Here we investigated the hypothesis that telomere length directly affects VSG switching. We demonstrate that telomerase deficient strains with short telomeres switch more frequently than genetically identical strains with long telomeres and that, when the telomere is short, switching preferentially occurs by GC. Our data supports the hypothesis that a short telomere at the active VSG expression site results in an increase in subtelomeric DNA breaks, which can initiate GC based switching. In addition to their significance for T. brucei and telomere biology, the findings presented here have implications for the many diverse pathogens that organize their antigenic genes in subtelomeric regions.

Vyšlo v časopise: Telomere Length Affects the Frequency and Mechanism of Antigenic Variation in. PLoS Pathog 8(8): e32767. doi:10.1371/journal.ppat.1002900
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002900

Souhrn

Zdroje

1. BarryJD, McCullochR (2001) Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite. Adv Parasitol 49: 1–70.

2. CrossGA (1975) Identification, purification and properties of clone-specific glycoprotein antigens constituting the surface coat of Trypanosoma brucei. Parasitology 71: 393–417.

3. PaysE (2005) Regulation of antigen gene expression in Trypanosoma brucei. Trends Parasitol 21: 517–520.

4. Hertz-FowlerC, FigueiredoLM, QuailMA, BeckerM, JacksonA, et al. (2008) Telomeric expression sites are highly conserved in Trypanosoma brucei. PLoS One 3: e3527.

5. Van der PloegLH, ValerioD, De LangeT, BernardsA, BorstP, et al. (1982) An analysis of cosmid clones of nuclear DNA from Trypanosoma brucei shows that the genes for variant surface glycoproteins are clustered in the genome. Nucleic Acids Res 10: 5905–5923.

6. BerrimanM, GhedinE, Hertz-FowlerC, BlandinG, RenauldH, et al. (2005) The genome of the African trypanosome Trypanosoma brucei. Science 309: 416–422.

7. MarcelloL, BarryJD (2007) Analysis of the VSG gene silent archive in Trypanosoma brucei reveals that mosaic gene expression is prominent in antigenic variation and is favored by archive substructure. Genome Res 17: 1344–1352.

8. WicksteadB, ErsfeldK, GullK (2004) The small chromosomes of Trypanosoma brucei involved in antigenic variation are constructed around repetitive palindromes. Genome Res 14: 1014–1024.

9. BerrimanM, HallN, SheaderK, BringaudF, TiwariB, et al. (2002) The architecture of variant surface glycoprotein gene expression sites in Trypanosoma brucei. Mol Biochem Parasitol 122: 131–140.

10. DeitschKW, LukehartSA, StringerJR (2009) Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat Rev Microbiol 7: 493–503.

11. HornD, BarryJD (2005) The central roles of telomeres and subtelomeres in antigenic variation in African trypanosomes. Chromosome Res 13: 525–533.

12. JohnsonPJ, BorstP (1986) Mapping of VSG genes on large expression-site chromosomes of Trypanosoma brucei separated by pulsed-field gradient electrophoresis. Gene 43: 213–220.

13. ZomerdijkJC, OuelletteM, ten AsbroekAL, KieftR, BommerAM, et al. (1990) The promoter for a variant surface glycoprotein gene expression site in Trypanosoma brucei. EMBO J 9: 2791–2801.

14. BorstP, UlbertS (2001) Control of VSG gene expression sites. Mol Biochem Parasitol 114: 17–27.

15. HornD, CrossGA (1997) Analysis of Trypanosoma brucei vsg expression site switching in vitro. Mol Biochem Parasitol 84: 189–201.

16. PaysE, GuyauxM, AertsD, Van MeirvenneN, SteinertM (1985) Telomeric reciprocal recombination as a possible mechanism for antigenic variation in trypanosomes. Nature 316: 562–564.

17. RudenkoG, McCullochR, Dirks-MulderA, BorstP (1996) Telomere exchange can be an important mechanism of variant surface glycoprotein gene switching in Trypanosoma brucei. Mol Biochem Parasitol 80: 65–75.

18. De LangeT, KooterJM, MichelsPA, BorstP (1983) Telomere conversion in trypanosomes. Nucleic Acids Res 11: 8149–8165.

19. HoeijmakersJH, FraschAC, BernardsA, BorstP, CrossGA (1980) Novel expression-linked copies of the genes for variant surface antigens in trypanosomes. Nature 284: 78–80.

20. MylerP, NelsonRG, AgabianN, StuartK (1984) Two mechanisms of expression of a predominant variant antigen gene of Trypanosoma brucei. Nature 309: 282–284.

21. PaysE, DelauwMF, Van AsselS, LaurentM, VervoortT, et al. (1983) Modifications of a Trypanosoma b. brucei antigen gene repertoire by different DNA recombinational mechanisms. Cell 35: 721–731.

22. BoothroydCE, DreesenO, LeonovaT, LyKI, FigueiredoLM, et al. (2009) A yeast-endonuclease-generated DNA break induces antigenic switching in Trypanosoma brucei. Nature 459: 278–281.

23. GloverL, McCullochR, HornD (2008) Sequence homology and microhomology dominate chromosomal double-strand break repair in African trypanosomes. Nucleic Acids Res 36: 2608–2618.

24. DreesenO, LiB, CrossGA (2007) Telomere structure and function in trypanosomes: a proposal. Nat Rev Microbiol 5: 70–75.

25. BernardsA, MichelsPA, LinckeCR, BorstP (1983) Growth of chromosome ends in multiplying trypanosomes. Nature 303: 592–597.

26. PaysE, LaurentM, DelinteK, Van MeirvenneN, SteinertM (1983) Differential size variations between transcriptionally active and inactive telomeres of Trypanosoma brucei. Nucleic Acids Res 11: 8137–8147.

27. LamontGS, TuckerRS, CrossGA (1986) Analysis of antigen switching rates in Trypanosoma brucei. Parasitology 92(Pt 2):355–367.

28. MylerPJ, AllenAL, AgabianN, StuartK (1985) Antigenic variation in clones of Trypanosoma brucei grown in immune-deficient mice. Infect Immun 47: 684–690.

29. TurnerCM (1997) The rate of antigenic variation in fly-transmitted and syringe-passaged infections of Trypanosoma brucei. FEMS Microbiol Lett 153: 227–231.

30. DreesenO, CrossGA (2008) Telomere length in Trypanosoma brucei. Experimental Parasitol 118: 103–110.

31. DreesenO, LiB, CrossGA (2005) Telomere structure and shortening in telomerase-deficient Trypanosoma brucei. Nucleic Acids Res 33: 4536–4543.

32. DreesenO, CrossGA (2006) Consequences of telomere shortening at an active VSG expression site in telomerase-deficient Trypanosoma brucei. Eukaryot cell 5: 2114–2119.

33. DreesenO, CrossGA (2006) Telomerase-independent stabilization of short telomeres in Trypanosoma brucei. Mol Cell Biol 26: 4911–4919.

34. LuriaSE, DelbruckM (1943) Mutations of Bacteria from Virus Sensitivity to Virus Resistance. Genetics 28: 491–511.

35. FieldMC, BoothroydJC (1996) Sequence divergence in a family of variant surface glycoprotein genes from trypanosomes: coding region hypervariability and downstream recombinogenic repeats. J Mol Evol 42: 500–511.

36. MorrisonLJ, MajiwaP, ReadAF, BarryJD (2005) Probabilistic order in antigenic variation of Trypanosoma brucei. Int J Parasitol 35: 961–972.

37. DeitschKW, MoxonER, WellemsTE (1997) Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections. Microbiol Mol Biol Rev 61: 281–293.

38. McEachernMJ, IyerS (2001) Short telomeres in yeast are highly recombinogenic. Mol Cell 7: 695–704.

39. RobinsonNP, BurmanN, MelvilleSE, BarryJD (1999) Predominance of duplicative VSG gene conversion in antigenic variation in African trypanosomes. Mol Cell Biol 19: 5839–5846.

40. HugN, LingnerJ (2006) Telomere length homeostasis. Chromosoma 115: 413–425.

41. LiS (2011) Cell-cycle-dependent telomere elongation by telomerase in budding yeast. Biosci Rep 31: 169–177.

42. LiS, MakovetsS, MatsuguchiT, BlethrowJD, ShokatKM, et al. (2009) Cdk1-dependent phosphorylation of Cdc13 coordinates telomere elongation during cell-cycle progression. Cell 136: 50–61.

43. WirtzE, LealS, OchattC, CrossGA (1999) A tightly regulated inducible expression system for conditional gene knock-outs and dominant-negative genetics in Trypanosoma brucei. Mol Biochem Parasitol 99: 89–101.

44. HirumiH, HirumiK (1989) Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. J Parasitol 75: 985–989.

45. DawkinsHJ, FerrierDJ, SpencerTL (1987) Field inversion gel electrophoresis (FIGE) in vertical slabs as an improved method for large DNA separation. Nucleic Acids Res 15: 3634–3635.

46. Munoz-JordanJL, CrossGA, de LangeT, GriffithJD (2001) t-loops at trypanosome telomeres. EMBO J 20: 579–588.