# The structural function of ATR in development, oncogenesis and cancer therapy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $421,825

## Abstract

PROJECT SUMMARY/ABSTRACT
Genomic instability drives cancer initiation, progression and treatment. The ATR kinase is a master regulator of
DNA damage responses (DDRs) during DNA replication and strand breaks. Although complete loss of ATR
(Atr-/-) abrogates embryonic development and cellular viability, ATR kinase inhibitors are well-tolerated in
preclinical trials and have generated promising therapeutic effects when used in combination with genotoxic
treatments including radiation. To determine whether ATR protein has a structural function in DNA replication
and repair (i.e., independent of its kinase activity or regulated by auto-phosphorylation), we generated a mouse
model expressing kinase-dead ATR protein (AtrKD). Atr+/KD mice are born at expected Mendelian ratio and of
normal size. Moreover somatic inactivation of the Atr conditional allele (AtrC) using Tamoxifen inducible Cre
recombinase is very well tolerated in AtrC/KD mice but not AtrC/- mice. While female Atr+/KD mice are fertile, Atr+/KD
male mice are sterile due to meiosis defects during spermatogenesis that were not seen in Atr+/- mice. Here we
propose to use the Atr null (Atr-), conditional (AtrC), and kinase-dead (AtrKD) mouse models to investigate
kinase-independent structural function during normal DNA replication and aging (aim 1), auto-phosphorylation
dependent dominant negative function of AtrKD protein during spermatogenesis(aim 2) and the oncogenic
potential as well as the chemo-sensitivity profile of the AtrKD mutation. Together, the results will elucidate the
structural functions of ATR during DNA repair and oncogenesis, and the mechanisms underlying the
therapeutic as well as side effects of ATR inhibition.

## Key facts

- **NIH application ID:** 9886205
- **Project number:** 5R01CA215067-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Shan Zha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,825
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886205

## Citation

> US National Institutes of Health, RePORTER application 9886205, The structural function of ATR in development, oncogenesis and cancer therapy (5R01CA215067-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9886205. Licensed CC0.

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