# Investigating PolQ-mediated alternative NHEJ in breast cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $425,096

## Abstract

Chromosomal rearrangements are a hallmark of cancer cells and constitute a major pathway by
which genes that affect tumor initiation and progression become mutated. Such aberrancies can
result from defects in double-stranded break (DSB) repair. There are three major pathways of DNA
repair in mammalian cells – the well-studied homology recombination (HR) and non-homologous
end joining (NHEJ) pathways, and the poorly characterized, yet highly error-prone alt-NHEJ
(alternative-NHEJ) pathway. Genetic rearrangements consistent with alt-NHEJ have been noted
both in spontaneous and therapy-related tumors. In this proposal we will focus on polymerase theta
(Polθ), a low-fidelity enzyme that we recently identified as a key factor that mediates DSB repair by
alt-NHEJ. Given that HR-defective tumors are “addicted” to repairing DSBs via the alt-NHEJ
pathway, we hypothesize that the mutagenic activity of Polθ help establish a genomic landscape
that is conducive for aggressive tumor behavior. Additionally, we predict that deleting Polθ in tumors
with mutations in the breast cancer susceptibility (BRCA) genes will sensitize cells to DNA damage-
inducing therapeutic agents, including radiation therapy, cisplatin and PARP inhibitors. In the
second aim, we will investigate the impact of ATM and PARP1 on Polθ is recruited to break sites
and how the polymerase modulates damage sites to promote erroneous repair. In addition, we will
pursue a proteomic-based approach to highlight the full spectrum of molecular players involved in
alt-NHEJ. Ultimately, a full understanding of the mechanistic basis of alt-NHEJ will provide a better
understanding of the source of genomic instability during the course of malignancy and guide more
effective treatment strategies for the increasing number of patients with HR mutated tumors.

## Key facts

- **NIH application ID:** 9850948
- **Project number:** 5R01CA229161-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Agnel Sfeir
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,096
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850948

## Citation

> US National Institutes of Health, RePORTER application 9850948, Investigating PolQ-mediated alternative NHEJ in breast cancer (5R01CA229161-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850948. Licensed CC0.

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