# Telomerase RNP Prisonbreaks from Phase-Separated Nuclear Body

> **NIH NIH R35** · RESEARCH INST OF FOX CHASE CAN CTR · 2024 · $470,000

## Abstract

Project Summary
Overview: The ribonucleoprotein enzyme telomerase maintains telomere length homeostasis – a shared
hallmark between aging and carcinogenesis. Insufficient telomerase leads to telomere dysfunctions and
replicative senescence in stem cells, precipitating short-telomere diseases. Conversely, telomerase is exploited
by ~90% of cancers for growth immortality. Activating promoter mutations in the reverse transcriptase (TERT)
gene ranks the most frequent non-coding driver mutations. We have made contributions to an understanding of
how telomerase and telomere can be modulated. 1) we uncovered that TCAB1, a non-catalytic subunit of
telomerase and a Cajal body (CB) trafficking protein, functions as an activity switch during telomerase catalysis.
Using next-gen RNA structural profiling, we found that TCAB1-bound RNPs are endowed with an RNA
conformation favorable for TERT-TR engagement, linking an RNA quality-control with RNP trafficking and
catalysis; 2) we showed that the 5’ TR cap hypermethylation plays a negative role in telomerase RNA
accumulation and activity. We can induce robust telomere elongation by genetic inactivation and chemical
inhibition of the cap hypermethylase TGS1; 3) we also discovered a crosstalk between snRNA 5’ and 3’ PTM
critical for global splicing fidelity and motor neuron viability in multiple organisms. 4) we uncovered a Toxic
telomerase RNP that provokes acute and selective cancer genotoxicity at telomeres, unlike the conventional
delayed killing by direct telomerase inhibition.
Goals: We will test a model that RNP assembly and/or activity can be limited by phase-separated CB. We have
found that dismantlement of the RNA and protein components of CB both led to GOF of telomerase. We are
addressing: 1) Can CB contribute to the molecular determinant of telomere length set points? we are testing this
with a novel optogenetic pipeline to manipulate phase separation of a subset of cellular CBs and monitor a single
telomere elongation; 2) What is the RNA basis for telomerase phase separation at CB, at telomeres, or when
mislocalized to nucleoli? We will improve the current icSHAPE-seq to determine RNA structure at subcellular
locations; 3) We aim to elucidate the mechanism by which phase separation sequesters telomerase RNPs,
focusing on the dynamic interplay between TCAB1 and Coilin; 4) we aim to understand the genotoxic mechanism
underly the Toxic TERT. We also use this as a tractable system to identify suppressors as potential new factors
in RNP assembly and targeting.
Vision: we will engineer tools to study structure-function of RNP within phase-separated bodies. We will identify
additional telomerase-like RNPs that are similarly governed by phase-separation, RNA QC, and RNA PTMs. Our
long-term goal is to develop novel chemical matters that can boost telomerase to improve cell therapy, such as
making exhaustion-resistant CAR-T; we aim to further develop our bifunctional telomerase-targeting molecule
that induces r...

## Key facts

- **NIH application ID:** 10877851
- **Project number:** 5R35GM150538-02
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Lu Chen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $470,000
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877851

## Citation

> US National Institutes of Health, RePORTER application 10877851, Telomerase RNP Prisonbreaks from Phase-Separated Nuclear Body (5R35GM150538-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10877851. Licensed CC0.

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