# Genome instability in cancer: telomeres and DNA repair

> **NIH NIH R35** · ROCKEFELLER UNIVERSITY · 2024 · $957,507

## Abstract

Project Summary
This project focuses on the role of telomeres and DSB repair in genome instability in cancer. Numerous recent
WGS studies have revealed that most cancer genomes carry a remarkable level of structural changes,
affirming the need to understand how this genome instability arises. In this context, our work asks how
telomeres affect tumorigenesis with emphasis on the two major contributions of telomeres in cancer: the
telomere tumor suppressor pathway and telomere-driven genome instability. During the current funding period,
we have provided genetic evidence for the telomere tumor suppressor pathway and showed that the correct
telomere length setting at birth prevents cancer in a wide range of tissues. We have dissected the mechanism
by which telomere crisis, a stage at which telomere shortening drives genome instability in checkpoint-deficient
cancer clones, instigates breakage-fusion-bridge (BFB) cycles, chromothripsis, and kataegis. We have
provided the first evidence that telomerase can create new telomeres (neotelomeres) at DSBs and propose
that neotelomere formation can mold the cancer genome by increasing the fitness of cells struggling with
ongoing BFB cycles. Finally, our lab continued its work on the role of 53BP1 in DSB repair and PARPi
treatment of BRCA1-deficient cells, showing that, unlike what was generally believed, 53BP1 does not block
resection but recruits the CST-Pola/primase complex to fill-in resected DNA ends. These findings set the stage
for our future work, in which we aim to continue our path-breaking research and the mentoring of future cancer
researchers. Examples of projects we will pursue are:
 1. Using an innovative approach, we will use CRISPRi screens for repressors of neotelomere
 formation and query hits for gene loss/mutation in cancer.
 2. Our proposal that neotelomere formation can terminate BFB cycles and enhance the viability of
 cells with dicentric chromosomes will be tested in an in vitro model for induction of BFB cycles.
 3. To gain deeper insights into the telomere tumor suppressor pathway, we will determine how
 telomere length is regulated.
 4. Following a recent demonstration that cancer cell lines with short telomeres are exceptionally
 sensitive to loss of the telomeric factors CST and TRF1, we will determine the mechanistic basis of
 these vulnerabilities in hopes that our insights may point to new treatments.
Our aim is to derive deep insights into how cancer genomes are altered with the overarching goal of providing
oncologists with information that can inform their decisions on diagnosis, treatment, and prevention.
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## Key facts

- **NIH application ID:** 10915563
- **Project number:** 5R35CA210036-09
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Titia de Lange
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $957,507
- **Award type:** 5
- **Project period:** 2016-09-02 → 2030-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915563

## Citation

> US National Institutes of Health, RePORTER application 10915563, Genome instability in cancer: telomeres and DNA repair (5R35CA210036-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10915563. Licensed CC0.

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