# Regulation of telomere recombination in ALT cancer cells

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $2,768

## Abstract

Project Summary
The unlimited replicative capacity of human tumor cells relies on their ability to
counteract the progressive loss of telomeric DNA that accompanies cell division. Eighty-
five percent of cancers achieve this by up-regulating telomerase, the enzyme that adds
telomere repeats to chromosome ends. The remaining 15% activate ALT (alternative
lengthening of telomeres), a recombination-based mechanism. The observation that ALT
is activated in a significant fraction of human tumors, combined with the notion that it
may provide an adaptive mechanism to anti-telomerase therapies, indicate it as an
important target for anti-cancer strategies. Recent studies identified the chromatin-
remodeling factor ATRX as the protein most frequently lost in ALT, but how this loss
impacts telomere recombination is not known. Our studies reveal a mechanism: loss of
ATRX suppresses resolution of sister telomere cohesion at mitosis. The resulting
persistent telomere cohesion promotes chromatid exchange between sister telomeres,
while it suppresses inappropriate recombination between non-sisters. We hypothesize
that persistent telomere cohesion is a critical component of the ALT cell state. In Aim 1
we will elucidate the mechanisms by which loss of ATRX promotes ALT cell
recombination and growth. In Aim 2 we will investigate how loss of ATRX leads to
activation of ALT. In Aim 3 we will explore the hypothesis that up-regulation of the
cohesin subunit SA1 in tumors promotes persistent telomere cohesion and an ALT-like
mechanism of telomere maintenance. Understanding how recombination mediates
telomere length maintenance in ALT cancers will provide insights into basic mechanisms
of recombination as well as provide targets for anti-cancer therapies.

## Key facts

- **NIH application ID:** 9748731
- **Project number:** 3R01CA200751-04S1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** SUSAN SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,768
- **Award type:** 3
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9748731

## Citation

> US National Institutes of Health, RePORTER application 9748731, Regulation of telomere recombination in ALT cancer cells (3R01CA200751-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9748731. Licensed CC0.

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