# Determining the role of TCAB1 in shaping telomerase function

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $463,270

## Abstract

Abstract
Impaired maintenance of telomeres by telomerase causes cellular senescence and underlies
many aging-related diseases in humans. Furthermore, telomere shortening is one of the most
reproducible hallmarks of aging in human tissues, suggesting that telomere dysfunction
contributes broadly to aging phenotypes in people. The human telomerase enzyme is
comprised of a catalytic core – the telomerase reverse transcriptase (TERT) and the telomerase
RNA component (TERC) – but also depends upon other holoenzyme proteins that bind the
H/ACA element within TERC. During evolution, vertebrate telomerase hijacked this H/ACA
sequence from other ancient non-coding RNAs, bringing the dyskerin core protein complex,
which recognizes the H/ACA element, and TCAB1, which binds the CAB box element, into the
telomerase holoenzyme. Telomerase function is critically dependent upon a series of steps,
including assembly of the enzyme, trafficking within the nucleus, recruitment to telomeres and
finally catalytic extension of telomeres. Each of these steps is poorly understood in humans and
each step can be disrupted by germline mutations in patients with telomere diseases. The
dyskerin complex is required for assembly and stability of telomerase. We identified TCAB1 as a
protein that interacts with dyskerin and showed that TCAB1 binds the CAB box element
common to TERC and to all small Cajal body RNAs (scaRNAs). We previously showed that
TCAB1 is required for localization of telomerase in Cajal bodies, required for telomere
maintenance and is important in recruitment to telomeres. We recently made the surprising
finding that TCAB1 is also critical for telomerase catalytic activity and that TCAB1 is required for
proper TERC conformation. Telomerase and other RNPs depend on an RNA molecule that
needs to fold in a precise conformation, and this correct conformation represents one of
countless potential structures. In this proposal, we pursue the hypothesis that TCAB1 is
essential in shaping the telomerase RNA, and that this activity of TCAB1 is conserved in the
splicing RNA pathway. We propose that the principal advantages conferred upon telomerase by
adopting an H/ACA RNA fate is facilitating assembly and proper folding of TERC, and that
numerous downstream steps depend upon this proper folding. We will pursue the following
aims: (1) To understand how telomerase catalytic function depends upon TCAB1 (2) To
determine how TCAB1 influences telomerase trafficking and recruitment (3) To determine how
TCAB1 loss affects scaRNA function and RNA splicing.

## Key facts

- **NIH application ID:** 9927965
- **Project number:** 5R01AG056575-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** STEVEN E ARTANDI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,270
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927965

## Citation

> US National Institutes of Health, RePORTER application 9927965, Determining the role of TCAB1 in shaping telomerase function (5R01AG056575-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9927965. Licensed CC0.

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