# Mechanism and Regulation of Telomerases

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $427,042

## Abstract

The reverse transcriptase telomerase elongates chromosome 3' ends by additional telomeric repeats,
compensating for repeat loss during conventional DNA replication. Restrictions of telomerase function
set an upper limit on human somatic tissue renewal, with consequences including immune deficiencies
from chronic infection and diseases of bone marrow failure, pulmonary fibrosis, and other disorders
from inherited telomerase subunit mutations. Inversely, constitutive over-activation of telomerase is
almost universally required for human cancer progression and metastasis.
 Telomerase is unique among polymerases in its reiterative copying of a hard-wired internal
template in the enzyme's integral RNA subunit. Also, unlike all other templated DNA polymerases,
telomerase must release product that is single-stranded rather than duplex in order to regenerate the
template and allow complementary-strand telomere synthesis. The elaborate catalytic cycle of repeat
synthesis required to support telomerase specialization is accomplished by intimate co-folding and
functional collaboration of telomerase reverse transcriptase (TERT) and telomerase RNA (TER). In
addition, telomerase activity at telomeres and telomerase cellular regulation require numerous other
subunits of cellular telomerase holoenzymes that are in general poorly characterized due to scarcity.
 The long-term objective of Collins lab NIGMS research funding is to determine the molecular and
biochemical principles that underlie telomerase enzyme mechanism and cellular action. These goals
inform fundamental principles of protein-nucleic acid interaction, ribonucleoprotein biogenesis and
function, nucleic acid synthesis, cellular proliferation control, genome stability, and tumorigenesis. The
strong Collins lab track record of insights supported by NIGMS funding emerges from parallel studies of
telomerase in two enabling model systems: the ciliate Tetrahymena and cultured human cells. Our
recent efforts have accomplished innovative telomerase reconstitutions that enable dissection of
enzyme mechanism; field-shifting discoveries of cellular telomerase holoenzyme subunits and their
functions; and truly landmark determinations of Tetrahymena and human telomerase holoenzyme
structures by cryo-EM, made possible by a wide range of accumulated expertise. Future studies will
build from this foundation towards the ultimate goal of enabling telomerase manipulation for clinical
therapeutics. In the near term, expanded cryo-EM studies of human telomerase throughout its catalytic
cycle, combined with other structural and biochemical assays, will identify the determinants of dynamic
nucleic acid handling necessary for telomeric repeat synthesis. We will also investigate the mechanism
of telomerase activation at telomeres and how telomerase synthesis of single-stranded DNA is coupled
to the complementary strand synthesis necessary for telomere stability.

## Key facts

- **NIH application ID:** 9859410
- **Project number:** 5R35GM130315-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Kathleen Collins
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,042
- **Award type:** 5
- **Project period:** 2019-04-01 → 2020-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859410

## Citation

> US National Institutes of Health, RePORTER application 9859410, Mechanism and Regulation of Telomerases (5R35GM130315-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9859410. Licensed CC0.

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