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The continued proliferation of human cells depends on the proper maintenance of the genomic information encoded in the 46 linear human chromosomes. The stability of these linear chromosomes depends on telomeres, which are maintained by telomerase.
Up-regulation of telomerase is found in more than 85% of human cancers, while telomerase insufficiency can cause early onset of human aging, highlighting the crucial role of telomerase regulation in both cancer therapy and human aging. On the one hand, we would like to inhibit overexpressed telomerase in tumor cells; on the other hand, we need to maintain the telomerase activity of normal stem cells to prevent early onset of aging.
My research goal is to elucidate mechanisms underlying the regulation of telomerase activity in cancer cells and normal stem cells, and to develop novel approaches for therapeutic intervention of human cancer and early onset of aging. Using both yeast and mammalian systems, I will focus on both (1) the regulation of telomerase activity by post-translational modification of telomerase and telomerase-related factors, and (2) the transcriptional regulation of human telomerase reverse transcriptase.
Liu CC, Ma DL, Yan TD, Fan X, Poon Z, Poon LF, Goh SA, Rozen SG, Ying Khee Hwang W, Tergaonkar V, Tan P, Ghosh S, Virshup DM, Goh EL, Li S. Distinct Responses of stem Cells to Telomere Uncapping - a Potential Strategy to Improve the Safety Of Cell Therapy.Stem Cells. 2016 Jun 14. doi: 10.1002/stem.2431. [Epub ahead of print]
Ramlee MK, Yan T, Cheung AM, Chuah CT, Li S. High-throughput genotyping of CRISPR/Cas9-mediated mutants using fluorescent PCR-capillary gel electrophoresis. Sci. Rep. 5:15587 (2015)
Koh CM, Khattar E, Leow SC, Liu CY, Muller J, Ang WX, Li Y, Franzoso G, Li S, Guccione E, Tergaonkar V. Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity. J Clin Invest. 125(5):2109-2122. (2015)
Akıncılar SC, Low KC, Liu CY, Yan TD, Oji A, Ikawa M, Li S, Tergaonkar V. Quantitative assessment of telomerase components in cancer cell lines. FEBS Lett. 589(9):974-984. (2015)
Liu C.C.; Gopalakrishnan V.; Poon L.P.; Yan T.D and S. Li. Cdk1 regulates the temporal recruitment of telomerase and CST complex for telomere replication. Molecular and Cellular Biology 34(1): 57-70 (2014)
Ho L.P.; Yit P.S.; Ng L.H.; Linn Y.C.; Zhao Y.; Sun Y.; Ling K.L.; Koh B.C.M.; Shih M.C.M.; Li S.; Wang X.Y.; Tien S.L. and Y.T. Goh. The road to memory: an early rest for the long journey. Journal of Immunology 191(11): 5603-14 (2013)
Bari S., Chu P.P.; Lim A.; Fan X.; Gay F.F.; Bunte, R.M.; Lim T.K.; Li S.; Chiu G.N. and W.Y. Hwang. Protective role of functionalized single walled carbon nanotubes enhance ex vivo expansion of hematopoietic stem and progenitor cells in human umbilical cord blood. Nanomedicine 9(8): 1304-1316 (2013)
Xu L., Li S. and B.A. Stohr The role of telomere biology in cancer. Annu. Rev. Pathol. 24(8): 49-78 (2013)
Ghosh A., Saginc G., Shin EM., Khattar E., Leow S.C., Yan T., Wong M., Zhang Z., Li G., Sung W.-K., Zhou J., Chng W.J., Li S, Liu E. and V. Tergaonkar. Telomerase directly regulates NFkB dependent transcription. Nature Cell Biology 14(12): 1270-1281 (2012)
Li S. Cell-cycle-dependent telomere elongation by telomerase in budding yeast. Bioscience Reports 3: 169-177 (2011)
Li S., Makovets S., Matsuguchi T., Blethrow J.D., Shokat K.M. and E.H. Blackburn. Cdk1-dependnt phosphorylation of Cdc13 coordinates telomere elongation during cell cycle progression. Cell 136: 50-61 (2009)
Li S., M. Nosrati and M. Kashani-Sabet. Knockdown of telomerase RNA using hammerhead ribozymes and RNA interference. Andrews, L.G. and Tollefsbol, T.O. (eds.), Methods in Molecular Biology: Telomerase inhibition-Strategies and Protocols. Humana Press 2007
Bagheri S., Nosrati M., Li S., Fong S., Torabian S., Rangel J., Moore D.H., Feerman S., Laposa R.R., Baehner F.L., Sagebiel R.W., Cleaver J.E. Haqq C., Debs R.J. Blackburn E.H. and Kashani-Sabet M. Genes and pathways downstream of telomerase in melanoma metastasis. Proc. Natl. Acad. Sci. USA 103: 11306-11311 (2006)
Li S., J. Crothers, C.M. Haqq and E.H. Blackburn. Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. J. Biol. Chem. 280:23709-23717 (2005)
Nosrati, M., Li S., S. Bagheri, D. Ginzinger, E.H. Blackburn, R.J. Debs, and M. Kashani-Sabet. Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. Clin Cancer Res. 10:4983-4990 (2004).
Li S., J.E. Rosenberg, A.A. Donjacour, I.L. Botchkina, Y.-K. Hom, G.R. Cunha and E.H. Blackburn. Rapid inhibition of cancer cell growth induced by lentiviral expression of mutant-template telomerase RNA constructs and anti-telomerase siRNA. Cancer Res 64: 4833-4840 (2004).
Zheng L., Pan H., Li S., Flesken-Nikitin A., Chen, P.-L., Boyer T.G., and Lee W.-H. Sequence-specific transcriptional co-repressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol. Cell. 6: 757-68 (2000).
Li S., Ting N.-S.Y., Zheng L., Ziv Y., Chen P.-L., Shiloh Y., Lee E.-Y. H., and Lee W.-H. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406: 210-215 (2000).
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