Telomerase is a specialized reverse transcriptase (RT) that synthesizes telomere DNA repeats at chromosome ends, using only a very short region of its intrinsic telomerase RNA (TR) subunit as template. This highly specialized function of telomerase relies on a special mechanism whereby the template RNA and the telomeric DNA dissociate and realign during the processive synthesis of repeats. However, the detailed mechanism of telomerase template translocation remains to be determined. This research program aims to articulate the unique mechanism of telomerase action and identify elements that regulate specific steps of template translocation. Although telomerase uses the single-stranded telomeric DNA as its native substrate, we have recently discovered that telomerase can act as a conventional RT utilizing RNA/DNA duplex as substrate. More surprisingly, telomerase recognizes the duplex substrate with a sequence-specificity. These crucial findings have provided great insights into the molecular mechanism of telomerase action. We hypothesize that duplex- binding and duplex-dissociation are important steps of the telomere-repeat synthesis cycle, and regulate telomere-repeat addition rate and processivity.
Specific Aims of the research program include (1) Determining the role duplex-binding affinity in template translocation efficiency, (2) Determining the rate-limiting step of template translocation, and (3) characterize the sequence- dependent termination of nucleotide addition by telomerase. We expect the outcomes of these experiments will greatly add to our understanding of telomerase mechanism.

Public Health Relevance

Project Narrative Telomerase is a specialized RNA-dependent DNA polymerase that adds DNA repeats to chromosome ends and viewed as an important drug target for anti-ageing and anti-cancer therapies. The goal of this research program is to understand the detailed mechanism of telomerase action, and identify elements and factors important for regulating telomerase function. Comprehension of the molecular mechanism of telomerase action will lay important foundations for finding cures to telomerase-related and telomere-mediated diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Gerratana, Barbara
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Arizona State University-Tempe Campus
Schools of Arts and Sciences
United States
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Chen, Yinnan; Podlevsky, Joshua D; Logeswaran, Dhenugen et al. (2018) A single nucleotide incorporation step limits human telomerase repeat addition activity. EMBO J 37:
Huang, Jing; Bley, Christopher J; Rand, Dustin P et al. (2017) In Vitro Preparation and Crystallization of Vertebrate Telomerase Subunits. Methods Mol Biol 1587:161-169
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Podlevsky, Joshua D; Chen, Julian J-L (2016) Evolutionary perspectives of telomerase RNA structure and function. RNA Biol 13:720-32
Podlevsky, Joshua D; Li, Yang; Chen, Julian J-L (2016) The functional requirement of two structural domains within telomerase RNA emerged early in eukaryotes. Nucleic Acids Res 44:9891-9901
Qi, Xiaodong; Rand, Dustin P; Podlevsky, Joshua D et al. (2015) Prevalent and distinct spliceosomal 3'-end processing mechanisms for fungal telomerase RNA. Nat Commun 6:6105
Huang, Jing; Bley, Christopher J; Rand, Dustin P et al. (2015) Sample Preparation of Telomerase Subunits for Crystallization. Bio Protoc 5:
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Brown, Andrew F; Podlevsky, Joshua D; Qi, Xiaodong et al. (2014) A self-regulating template in human telomerase. Proc Natl Acad Sci U S A 111:11311-6

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