Team:Nanjing NFLS/Project
Project.
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Background— telomere, telomerase, and cancer.
The human telomere consists of many repetitive TTAGGG sequences, which play important roles in chromosome protection, positioning and replication (1, 2). Telomeres terminate with a 3′ single-stranded overhang that is bound by multiple variant proteins, which is essential for both telomere maintenance and capping (3). The eukaryotic DNA replication machinery can’t replicate the extreme ends of chromosomes, causing gradually shortened chromosomes along with cell division. In order to repair the incomplete telomere in some special cells, a specialized protein named as telomerase has been developed. Telomerase is a natural RNA- containing enzyme that can synthesize the repetitive telomeric sequences (4), which thus helps to maintain the integrity of the genome in some cells such as embryonic stem cells (5). Telomerase is silenced in most normal tissue cells but is reactivated in most human cancer cells (6, 7), suggesting that telomerase may be a good target for cancer therapy (8, 9). Therefore, many telomerase inhibitors have been developed to treat cancers; however, their side effects determine that none of them has become any applicable clinical drug (9-11).
Goodbye, side effects!
Our project aims at eliminating the side effects of cancer therapy using a telomerase-activated gene expression system (Tage system) to target and induce the apoptosis of cancer cells. We conceive this therapy take effect through intravenous injection only .
Our design
Go to our front page to read the abstract.
We designed a telomerase-activating gene expression system to induce cancer cell death. In this system, a vector ended with a telomerase-recognizable end can be elongated by telomerase, which will provide a telomeric repeat sequence that can be bound by a telomeric DNA-targeting dCas9-VP64-sgRNA. This binding will activate expression of an effector gene Cas9. The produced Cas9 protein can then be guided to the telomeres of cancer cell chromosomes by a telomere-targeting sgRNA, which will produce the DNA damage and lead to cancer cell death.
Still not quite clear? Watch the video!
For details of this system, go on to check out the experiments.
Reference.
1. E. H. Blackburn, Cell 37, 7 (1984).
2. E. H. Blackburn, Nature 350, 569 (1991).
3. T. L. Williams, D. L. Levy, S. Maki-Yonekura, K. Yonekura, E. H. Blackburn, J. Biol. Chem. 285, 35814
(2010).
4. T. Aschacher et al., Oncogene 35, 94 (2016).
5. Y. Deng, S. Chang, Lab. Invest. 87, 1071 (2007).
6. W. E. Wright, M. A. Piatyszek, W. E. Rainey, W. Byrd, J. W. Shay, Dev. Genet. 18, 173 (1996).
7. J. W. Shay, W. E. Wright, Semin. Cancer Biol. 21, 349 (2011).
8. F. W. Huang et al.,Science 339, 957 (2013).
9. M. A. Jafri, S. A. Ansari, M. H. Alqahtani, J. W. Shay, Genome Med.8, 69 (2016).
10. G. Mosoyan et al. , Leukemia 31, 2458 (2017).
11. A. Tefferi et al., N. Engl. J. Med. 373, 908 (2015).
12. N. W. Kim et al., Science 266, 2011 (1994).
13. S. J. Diede, D. E. Gottschling, Cell 99, 723 (1999).