# Genome instability in cancer: telomeres and DNA repair

> **NIH NIH R35** · ROCKEFELLER UNIVERSITY · 2020 · $1,017,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Recent sequencing data has revealed an unanticipated level of genomic instability in cancer. The origin of
these changes is largely unknown. This proposal focuses on two aspects of the maintenance of genome
integrity relevant to cancer: telomere dysfunction and DNA repair. We propose to examine the molecular basis
of the telomere tumor suppressor pathway whereby telomere attrition leads to dysfunctional telomeres and
proliferative arrest. These experiments will make use of normal human epithelial cells in which critical genes
have been removed with CRISPR/Cas9 genome editing and will apply innovative imaging of telomere structure
using super-resolution STORM imaging in combination with expansion microscopy. When the telomere tumor
suppressor pathway fails because of the loss of p53 and Rb, telomeres continue to shorten during early tumor
development, leading to large numbers of dysfunctional telomeres and genome instability (referred to as
telomere crisis). We propose to determine the changes in the genome that result from progression through
telomere crisis. These experiments will involve a new in vitro model for telomere crisis in epithelial cells
combined with whole genome sequencing. Finally, we propose to study the mechanism of double-strand break
(DSB) repair, which is carefully regulated to maintain genome integrity. In particular, we will focus on the
mechanism by which 53BP1 represses the resection of DSBs and promotes their mobility using the mouse
model systems we have developed and new technologies for the analysis of chromatin structure (ATAC
sequencing) and locus position (DamID-LaminB1 marking). These two attributes of 53BP1 are highly relevant
to the induction of lethal genome instability resulting from inhibition of the PARP1 poly(ADP-ribose) polymerase
in BRCA-deficient cells. Collectively, the proposed experiments will illuminate new aspects of genome
instability in cancer. The objective of these studies is to gain insights that will ultimately inform and guide
decisions in the cancer clinic.

## Key facts

- **NIH application ID:** 10006509
- **Project number:** 5R35CA210036-05
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Titia de Lange
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,017,000
- **Award type:** 5
- **Project period:** 2016-09-02 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006509

## Citation

> US National Institutes of Health, RePORTER application 10006509, Genome instability in cancer: telomeres and DNA repair (5R35CA210036-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006509. Licensed CC0.

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