Center for Gene Regulation in Health and Disease (GRHD)

Bibo Li

Telomeres are nucleoprotein complexes located at ends of linear chromosomes. Although telomeres do not contain any genes, they play a pivotal role in protection of the chromosome ends from illegitimate DNA recombination, repair and nucleolytic activities. Therefore, telomeres are essential for genome stability. Conventional DNA polymerases cannot fully replicate the end of linear DNA molecules, and telomeres are expected to shorten after each round of DNA replication, causing the so-called "end replication problem". Most organisms use a ribonucleoprotein, telomerase, to synthesize telomere DNA de novo, which can maintain a stable telomere length homeostasis. Telomeres often form a heterochromatic structure that can suppress the expression of genes located at subtelomeric regions. Interestingly, in quite a few microbial pathogens that undergo antigenic variation, genes encoding surface antigens that are essential for pathogen virulence are located at subtelomeric regions, suggesting that telomeres play an important role in regulation of antigenic variation.

My lab is interested in studying telomere functions in Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis, which is fatal without treatment. Current anti-trypanosome drugs are highly toxic, which greatly limits their efficacy. T. brucei regularly switches to express different major surface antigens (VSGs) to evade their mammalian host immune responses. This antigenic variation is critical for T. brucei long-term infection and parasite virulence. All VSGs are expressed from loci adjacent to telomeres. Our lab has demonstrated that telomere proteins play important roles in regulation of subtelomeric VSG expression and switching (Yang et al. 2009. Cell 137:99; Pandya et al. 2013. NAR 41:7673; Jehi et al. 2014. Cell Research 24:870). We are currently investigating the mechanisms of how telomere proteins are involved in regulation of antigenic variation.

1.    Bibo Li and A. J. Lustig. (1996) A novel mechanism for telomere size control in Saccharomyces cerevisiae. Genes Dev. 10: 1310-1326. 

2.    Bibo Li, S. Oestreich and T. de Lange. (2000) Identification of human Rap1: implications for telomere evolution. Cell 101: 471-483. 

3.    H. Scherthan, M. Jerratsch, Bibo Li, S. Smith, M. Hulten, T. Lock and T. de Lange. (2000) Mammalian meiotic telomeres: protein composition and their redistribution in relation to nuclear pores. Mol. Biol. Cell 11: 4189-4203.

4.    S. Hanaoka, A. Nagadoi, S. Yoshimura, S. Aimoto, Bibo Li, T. de Lange, and Y. Nishimura. (2001) NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA binding domains. J. Mol. Biol. 312: 167-175. 

5.    Bibo Li and T. de Lange. (2003) Rap1 affects the length and heterogeneity of human telomeres. Mol. Biol. Cell 14: 5060-5068. 

6.    Bibo Li, A. Espinal, and G. A. M. Cross. (2005) Trypanosome telomeres are protected by a homologue of mammalian TRF2. Mol. Cell. Biol. 25: 5011-5021.

7.    O. Dreesen, Bibo Li, and G. A. M. Cross. (2005) Telomere structure and shortening in telomerase-deficient Trypanosoma brucei. Nucleic Acids Res. 33: 4536-4543. 

8.    O. Dreesen, Bibo Li, and G. A. M. Cross. (2007) Telomere structure and function in trypanosomes: a proposal. Nature Review Microbiology 5:70-75.

9.    X. Yang, L. M. Figueiredo, A. Espinal, E. Okubo, and Bibo Li* (2009). Rap1 is essential for silencing telomeric Variant Surface Glycoprotein genes in Trypanosoma brucei. Cell 137: 99-109. Featured on the journal cover.

10. I. S. Joseph, A. Kumari, M. K. Bhattacharyya, H. Gao, Bibo Li, and Arthur J. Lustig (2010) An mre11 mutation that promotes telomere recombination and an efficient bypass of senescence. Genetics 185:761-770. 

11. Bibo Li* (2010) A newly discovered role of telomeres in an ancient organism – Extraview on “Rap1 is essential for silencing telomeric Variant Surface Glycoprotein genes in Trypanosoma brucei.” Nucleus. 1(3): 260-263. 

12. R. Sandhu and Bibo Li* (2011) Examination of the Telomere G-overhang Structure in Trypanosoma brucei. JoVE. http://www.jove.com/details.php?id=1959

13. R. Lama, R. Sandhu, B. Zhong, Bibo Li*, and Bin Su* (2012) Identification of selective tubulin inhibitors as potential anti-trypanosomal agents. Bioorganic & Medicinal Chemistry Letters. doi: http://dx.doi.org/10.1016/j.bmcl.2012.07.023

14. Bibo Li*. (2012). Telomere components as potential therapeutic targets for treating microbial pathogen infections. Frontiers in Oncology. 2: Article 156. doi: 10.3389/fonc.2012.00156.

15. Bibo Li*. (2012). Chapter 8: Telomere as an important player in regulation of microbial pathogen virulence. In “Reviews on Selected Topics of Telomere Biology”. Edited by Bibo Li.  ISBN 978-953-51-0849-8, Published by InTech.

16. I. Benmerzouga, J. Concepción-Acevedo, H.S. Kim, A.V. Vandoros, G.A.M. Cross, M.M. Klingbeil, and Bibo Li*. (2013) Trypanosoma brucei Orc1 Is Essential for Nuclear DNA Replication and Affects Both VSG Silencing and Switching. Molecular Microbiology. 87:196-210. 

17. R. Sandhu, S. Sanford, S. Basu, M. Park, U. M. Pandya, K. Chakrabarti*, Bibo Li*. (2013) A Trans-spliced Telomerase RNA Dictates Telomere Synthesis in Trypanosoma brucei. Cell Research. 23:537-551. 

18. U. M. Pandya, R. Sandhu, and Bibo Li*. (2013) Silencing subtelomeric VSG by Trypanosoma brucei RAP1 at the insect stage involves chromatin structure changes. Nucleic Acid Research. 41:7673-7682. 

19. T. Mazumdar, R. Sandhu, M. Qadan, J. DeVecchio, V. Magloire, A. Agyeman, Bibo Li, and J. A. Houghton. (2013) Hedgehog signaling regulates telomerase reverse transcriptase in human cancer cells. PLoS One. 10.1371/journal.pone.0075253.

20. S. Jehi, F. Wu, and Bibo Li*. (2014) Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity. Cell Research. 24:870-885.

21. B. Zhong, R. Lama, Bibo Li*, and B. Su*. (2014) Lead optimization of dual tubulin and Hsp27 inhibitors. European Journal of Medicinal Chemistry. 80:243-253.

22. S. Jehi, X. Li, R. Sandhu, F. Ye, I. Benmerzouga, M. Zhang, Y. Zhao*, and Bibo Li*. Suppression of subtelomeric VSG switching by T. brucei TRF requires its TTAGGG repeat-binding activity. Revision being reviewed at Nucleic Acid Research.

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