# Understanding Telomere Elongation Mechanisms in Cancer

> **NIH NIH F30** · YALE UNIVERSITY · 2022 · $31,607

## Abstract

Project Summary
Malignant cancers must activate telomere maintenance mechanisms to achieve replicative immortality.
Mutations in the human Protection Of Telomeres 1 (hPOT1) protein are frequently detected in cancers with
abnormally long telomeres. This result suggests that the loss of hPOT1 function disrupts regulation of telomere
length homeostasis to promote telomere elongation. The mouse genome encodes two POT1 proteins, POT1a
and POT1b. I have generated Pot1b null tumors that display markedly elongated telomeres mediated by
telomerase. In Aim 1, I will measure telomerase expression and its recruitment to telomeres to determine if
changes in telomerase dynamics has led to telomere length increase in these tumors. Then I will investigate the
mechanism underlying changes in telomerase dynamics by testing the role of DDR observed in Pot1b null tumors
and the role of POT1b-TPP1 interactions in telomerase-mediated length maintenance.
 Pot1b null tumors also display very heterogeneous telomere length with extremely long ss G-overhang
that is reminiscent of telomeres generated by Alternative Lengthening of Telomeres (ALT), a telomere length
maintenance pathway through homology directed repair and independent of telomerase function. When Pot1b
loss is combined with telomerase deletion, telomeres rapidly shorten and potentially select for ALT activation.
Aim 2 will test for activation of the ALT maintenance in Pot1b-/-; Tert-/- MEFs. I will also determine if the Pot1b-/-;
Tert-/-; Atrx-/- genetic background is sufficient to activate ALT. Furthermore, I will reconstitute POT1b domain
mutants in ALT positive cells to investigate the mechanisms utilized by POT1b to repress ALT. Finally, I will
perform RNA-seq to identify novel factors contributing to ALT activation in Pot1b-/-; Tert-/- MEFs.
 Together, these aims explore the central hypothesis that POT1b represses the activation of telomere
maintenance mechanisms. Aim 1 will investigate the mechanism leading to telomerase-mediated telomere
hyper-elongation in the absence of POT1b and Aim 2 will determine if the combined loss of POT1b and TERT
activates ALT. Completion of these aims will contribute to our knowledge of the telomere maintenance
mechanisms necessary to promote replicative immortality and cancer initiation.

## Key facts

- **NIH application ID:** 10364650
- **Project number:** 5F30CA254123-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Taylor Nicholas Takasugi
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,607
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364650

## Citation

> US National Institutes of Health, RePORTER application 10364650, Understanding Telomere Elongation Mechanisms in Cancer (5F30CA254123-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10364650. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*