Studies on Telomerase Regulation.
Telomeres are the physical ends of chromosomes encrypted by a repeat DNA sequence (TTAGGG). In normal human cells, telomeres erode with each cell division because they lack telomerase, a reverse transcriptase that maintains the telomere. In most somatic cells, telomere erosion leads to cell death thereby removing senescent cells from the replicative pool. The telomere 'ticketing' process is dysfunctional in many cancer cells because telomerase is maintained when it should not be. Regulation of telomerase activity and telomere homeostasis is therefore fundamentally important in growth control. We have new evidence that human telomerase is regulated by the ubiquitin/proteasome pathway, a pathway that degrades and recycles proteins. New data reveal that the catalytic subunit of telomerase, hTERT, is post-translationally modified by ubiquitin and directed to the 26S proteasome for degradation. An hTERT specific E3 ligase gene has been identified and cloned from humans. This gene is identical to a well conserved and ancient gene called makorin-1, the founding member of a large gene family of unknown function. There are at least 10 makorin genes in the human genome and makorin-1 (MKRN1) encodes a RING-zinc finger protein that catalyzes the ligation of ubiquitin to hTERT. We have shows that high levels of MKRN1 expression in cancer cells lead to the loss telomere DNA and telomerase. The ultimate goal of this research is to identify novel targets for therapeutic intervention in cancer and to explore how the proteasome pathway mechanistically impacts telomere biology.
References on the telomere project:
Kang, M.R, Muller, M.T. and In Kwon Chung. (2004) Telomeric DNA Damage by Topoisomerase I: A possible mechanism for cell killing by camptothecin. J. Biol. Chem., Mar 2004; 279: 12535 – 12541
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Lee, G.E., Yu, E., Cho, C., Lee, J., Muller, M., Chung, I. (2004). DNA-PKcs interacting protein KIP binds telomerase through interaction with hTERT. J. Biol. Chem. 279: 34750-5
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Kim, J, Park S., Kang, M, Oh S., Lee, T and Muller, M and Chung, I. (2005) Ubiquitin ligase MKRN1 modulates telomere length homeostasis through proteolysis of hTERT. Genes and Development 19:776-781. 
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Salvatico, J., and Muller, M. (2010) Makorin1 is a Ubiquitin Ligase Induced during Differrentiation Results in degradation of hTERT. Molec. Cell. Biochem 342:241-250.
http://www.springerlink.com/content/j150x70116740824/
Interested in applying for graduate studies in Dr. Muller’s laboratory? We have an exciting array of projects (research projects). For more information regarding UCF and the application process, prospective graduate students may go to this link:
www.graduate.ucf.edu. You may also contact us directly at biomoldoc@mail.ucf.edu
Dr. Mark T. Muller, Ph.D.
Professor of Molecular Biology and Microbiology
University of Central Florida
College of Medicine
Biomolecular Research Annex
12722 Research Parkway
Orlando, FL 32826-3227
Office: 407-882-2268
Lab: 407-882-2267
Fax: 407-384-2062
Information about Research Areas at UCF Burnett School of Biomedical Sciences:
http://www.youtube.com/ucf#p/u/0/FhIus-3E79c