Telomerase is required for the maintenance of telomere length. In the absence of telomerase, telomeres shorten progressively. In primary fibroblasts telomere shortening triggers cellular senescence. This limited replicative potential may protect cells from immortalization and limit tumor growth. Telomerase is expressed at higher levels in cancer cells than somatic cells. Deletion of telomerase in mice can lead to a reduction in tumors. Telomerase is thus a prime candidate for cancer chemotherapy. Telomerase is also essential for the long-term growth of stem cells. Defects in telomerase lead to telomere shortening and stem cell failure diseases in humans. We are studying the biochemistry of telomerase and telomere processing to understand the fundamental molecular processes required for telomere length maintenance. Telomerase is a unique kind of polymerase that also contains an essential RNA component. The RNA component provides a template for the telomere repeats synthesized by telomerase. In addition, there are functional regions in the RNA that contribute to enzyme catalysis. The protein component, TElomerase Reverse Transcriptase, TERT, has a catalytic core with similarity reverse transcriptases. The domain structure and mutational analysis predict a single catalytic site for nucleotide addition. We would like to understand how the tightly bound telomerase RNA is used reiteratively as a template by copying from a single catalytic site. Further we would like to know how regions of the telomerase RNA distant from the template influence the catalytic reaction. To better understand the roles of the RNA and the protein component in elongation, we will purify the components of telomerase and study their biochemical interactions. In addition, to fully understand the regulation of telomerase elongation in vivo, we will characterize the telomere processing that creates the molecular end that is recognized by telomerase. Understanding telomerase structure, function and regulation at this molecular level will allow new approaches to both telomerase inhibition and/or telomerase activation that influence cell growth and viability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG009383-20
Application #
7795133
Study Section
Special Emphasis Panel (ZRG1-NDT-K (01))
Program Officer
Mccormick, Anna M
Project Start
1991-09-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
20
Fiscal Year
2010
Total Cost
$439,932
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Greider, Carol W (2016) Regulating telomere length from the inside out: the replication fork model. Genes Dev 30:1483-91
Lee, Stella Suyong; Bohrson, Craig; Pike, Alexandra Mims et al. (2015) ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells. Cell Rep 13:1623-32
Tom, Hui-I Kao; Greider, Carol W (2010) A sequence-dependent exonuclease activity from Tetrahymena thermophila. BMC Biochem 11:45
Chen, Jiunn-Liang; Greider, Carol W (2005) Functional analysis of the pseudoknot structure in human telomerase RNA. Proc Natl Acad Sci U S A 102:8080-5; discussion 8077-9
Chen, Jiunn-Liang; Greider, Carol W (2003) Determinants in mammalian telomerase RNA that mediate enzyme processivity and cross-species incompatibility. EMBO J 22:304-14
Chen, Jiunn-Liang; Greider, Carol W (2003) Template boundary definition in mammalian telomerase. Genes Dev 17:2747-52
Chen, Jiunn-Liang; Opperman, Kay Keyer; Greider, Carol W (2002) A critical stem-loop structure in the CR4-CR5 domain of mammalian telomerase RNA. Nucleic Acids Res 30:592-7
Le, S; Sternglanz, R; Greider, C W (2000) Identification of two RNA-binding proteins associated with human telomerase RNA. Mol Biol Cell 11:999-1010
Le, S; Zhu, J J; Anthony, D C et al. (1998) Telomerase activity in human gliomas. Neurosurgery 42:1120-4;discussion 1124-5
Greider, C W (1996) Telomere length regulation. Annu Rev Biochem 65:337-65

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