# Molecular Mechanisms of Telomerase Catalysis and its Recruitment to Telomeres

> **NIH NIH R00** · MICHIGAN STATE UNIVERSITY · 2020 · $249,000

## Abstract

Summary/Abstract
Human chromosomes end in telomeres, repetitive DNA sequences that are bound by the Shelterin
protein complex (1). During semi-conservative DNA replication the extreme ends of a chromosome are
unable to be duplicated, leading to successive chromosome shortening. Once telomeres reach a critical
length, cells enter senescence or undergo apoptosis (2). To counteract chromosome shortening,
continuously dividing cells, such as germ cells, stem cells, and most cancer cells, express telomerase,
an RNA-containing reverse transcriptase (3). Telomerase is a unique enzyme that processively adds
telomeric repeats, copied from its RNA component, to the single-stranded DNA overhang of
chromosome ends (4). The molecular mechanisms that govern telomerase processivity are poorly
defined, but are critical to understand telomere maintenance.
 The Shelterin complex carries out two key functions at telomeres; it prevents telomeres from
being recognized as sites of DNA damage, and it recruits telomerase to telomeres (5,6). Telomerase
recruitment to telomeres is a tightly regulated process. Telomerase resides in Cajal bodies, specialized
RNA-processing compartments in the nucleus, throughout most of the cell cycle. During S-phase,
telomerase is recruited to telomeres to maintain telomere length (7). Although the protein-protein
interactions required for telomerase to associate with telomeres are well understood, the spatio-
temporal control of telomerase recruitment is poorly defined (7). Potential mechanisms for regulating
telomerase recruitment include alterations in composition of telomerase and the shelterin complex or
post-translational modification of its components.
 Telomere maintenance plays an important role in multiple human diseases. Deficiencies in
telomerase assembly, activity, or recruitment to telomeres cause dyskeratosis congenita, pulmonary
fibrosis, and aplastic anemia, severe human conditions characterized by stem cell failure (8). In
addition, 90% of cancers rely on telomerase activity to allow them to divide indefinitely (9). Therefore,
understanding the basic biology of telomerase recruitment to telomeres and telomerase catalysis could
lead to novel approaches to modulate this process as a therapeutic approach for several human
diseases. I propose to analyze the molecular mechanisms underlying telomerase recruitment to
telomeres and telomerase catalysis using genome editing and a combination of cell biological,
proteomic, biochemical, and single-molecule approaches. In particular I will:
1. Determine the molecular mechanisms that drive telomerase recruitment to telomeres in S-
Phase. Using genome-edited cell lines expressing tagged telomerase and shelterin components, I will
conduct live cell imaging of telomerase trafficking to telomeres, analyze the assembly state of
telomerase and the shelterin complex throughout the cell cycle using cell biological and proteomic
approaches, and identify kinases that modulate telomerase traffic...

## Key facts

- **NIH application ID:** 9898387
- **Project number:** 5R00GM120386-05
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Jens Christopher Schmidt
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2016-08-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898387

## Citation

> US National Institutes of Health, RePORTER application 9898387, Molecular Mechanisms of Telomerase Catalysis and its Recruitment to Telomeres (5R00GM120386-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898387. Licensed CC0.

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