Center for Gene Regulation in Health and Disease (GRHD)

Bibo Li

SR 253

Telomeres are nucleoprotein complexes located at chromosome ends. 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 (which is important for preventing tumorigenesis in humans). Conventional DNA polymerases cannot fully replicate the endd of linear DNA molecules, and telomeres are expected to shorten after each round of DNA replication, causing the so-called "end replication problem" (which is an important cellular senescence mechanism in human somatic cells and has been implicated in organismal aging). Most organisms use a ribonucleoprotein, telomerase, to synthesize telomere DNA de novo, which helps maintain a stable telomere length homeostasis. Telomerase is a specialized reverse transcriptase that includes a catalytic protein subunit (TERT) and an RNA subunit (TR) that provides the template for telomeric DNA synthesis. Telomere maintenance mechanisms (including the telomerase-mediated telomere synthesis) are essential for unlimited cell proliferative ability. In addition, telomeres often form a heterochromatic structure that suppresses the expression of genes located at subtelomeric regions, a phenomenon often called telomeric silencing. Furthermore, regions immediately upstream of the telomeres, termed subtelomeres, are often fragile sites that experience relatively more frequent DNA recombination than most chromosome internal 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, presumably taking advantage of the plastic nature of  subtelomeres.

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 the mammalian host immune response. This antigenic variation is critical for T. brucei long-term infection and parasite virulence. All VSGs are expressed from loci adjacent to telomeres in a strictly monoallelic manner. Our lab has demonstrated that telomere proteins play essential roles in regulation of subtelomeric VSG expression/silencing (Yang et al. 2009. Cell 137:99; Pandya et al. 2013. NAR 41:7673). Although T. brucei subtelomeres are fragile, which presumably facilitates VSG switching, subtelomere integrity is also critical for T. brucei survival. We recently found that telomere proteins are essential for maintaining subtelomere stability, which in turn influence VSG switching (Jehi et al. 2014. Cell Res. 24:870; Jehi et al. 2014. NAR 42:12899; Jehi et al. 2016. PLoS One. 11: e0156746; Nanavaty et al. 2017. NAR in press). We are currently investigating the detailed mechanisms of exactly how telomere proteins regulate subtelomeric VSG expression/silencing and how telomere proteins help maintain subtelomere integrity and stability. Our work on T. brucei telomere protein TbRAP1 is funded by an NIH R01 grant (AI066095, PI: Li).

We have also identified the T. brucei telomerase RNA gene (TbTR) as a collaboration with Dr. Kausik Chakrabarti at Carnegie Mellon University (Sandhu et al. 2013. Cell Res. 23:537). We are currently investigating the function and structure of TbTR, and this work is supported by an NSF grant (PI: Li & Chakrabarti).

Additionally, we are collaborating with Dr. Bin Su in the Chemistry Department at Cleveland State University to develope tubulin inhibitors that specifically inhibits T. brucei growth without affecting host cells. Our work has resulted in identification of several lead compounds that can inhibit T. brucei growth effectively both in vitro and in vivo (Lama et al. 2012. Bioorg Med Chem Lett. 22:5508; Zhong et al. 2014. Eur. J. Med. Chem. 80:243; Nanavaty et al. 2016. PLoS One. 11:e0146289). This project is supported by an NIH R15 grant (AI103889, PI: Su).

1.    Bibo Li and A. J. Lustig (1996) A novel mechanism for telomere size control in Saccharomyces cerevisiae. Genes Dev. 10: 1310-1326. PMID: 8647430.

2.    Bibo Li, S. Oestreich and T. de Lange (2000) Identification of human Rap1: implications for telomere evolution. Cell 101: 471-483. PMID: 10850490.

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. PMID: 11102517.


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. PMID: 11545594.

5.    Bibo Li and T. de Lange (2003) Rap1 affects the length and heterogeneity of human telomeres. Mol. Biol. Cell 14: 5060-5068. PMID: 14565979.

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. PMID: 15923618.

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. PMID: 16091631.

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. PMID: 17160000.

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. PMID: 19345190.

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. PMID: 20421597.

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. PMID: 21327073.

12. R. Sandhu and Bibo Li* (2011) Examination of the Telomere G-overhang Structure in Trypanosoma brucei. JoVE. PMID: 21307825.

13. R. Lama, R. Sandhu, B. Zhong, Bibo Li*, and Bin Su* (2012) Identification of selective tubulin inhibitors as potential anti-trypanosomal agents. Bioorg Med Chem Lett. 22:5508-5516. PMID: 22850214.

14. Bibo Li* (2012) Telomere components as potential therapeutic targets for treating microbial pathogen infections. Frontiers in Oncology. 2: 156. doi: 10.3389/fonc.2012.00156. PMID: 23125966.

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. PMID: 23216794.

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. PMID: 23478302.

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. PMID: 23804762.

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. PMID: 24086482.

20. S. Jehi, F. Wu, and Bibo Li* (2014) Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity. Cell Research. 24:870-885. PMID: 24810301.

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. PMID: 24780601.

22. S. Jehi, X. Li, R. Sandhu, F. Ye, I. Benmerzouga, M. Zhang, Y. Zhao*, and Bibo Li* (2014) Suppression of subtelomeric VSG switching by Trypanosoma brucei TRF requires its TTAGGG repeat-binding activity. Nucleic Acid Research. 42:12899-12911. PMID: 25313155.

23. Bibo Li. (2015) DNA Double-Strand Breaks and Telomeres Play Important Roles in Trypanosoma brucei Antigenic Variation. Eukaryotic Cell. 14:196. PMID: 25576484.

24. V. Nanavaty, R. Lama, R. Sandhu, B. Zhong, D. Kulman, V. Bobba, A. Zhao, B. Li*, B. Su*. (2016) Orally active and selective tubulin inhibitors as anit-trypanosome agents. PLoS One. 11:e0146289.

25. S. Jehi, V. Nanavaty, Bibo Li*. (2016) Trypanosoma brucei TIF2 and TRF Suppress VSG Switching Using Overlapping and Independent Mechanisms. PLoS One. 11(6): e0156746.

26. V. Nanavaty, R. Sandhu, S. Jehi, U. Pandya, Bibo Li*. (2017). Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids. Nucleic Acid Research. In press.

* Corresponding author.