# ATM and DNA Damage in the Nervous System

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $392,656

## Abstract

Abstract.
Genome stability is critically important for human health. This is apparent from the myriad of inherited human
syndromes characterized by defective DNA damage responses. The nervous system is particularly prone to the
consequences of genome damage, which can lead to neurodegeneration or neurodevelopmental disorders.
Defects in genome maintenance are also increasingly being linked to broader neurologic health issues, including
age-related neurodegenerative events that mar cognitive ability and quality of life. Therefore, understanding the
mechanistic connections between faulty DNA damage signaling and human disease is of fundamental
biomedical importance. The neurodegenerative syndrome ataxia telangiectasia (A-T), which results from loss
of function of the DNA damage-signaling serine/threonine kinase ATM (ataxia telangiectasia, mutated),
exemplifies the importance of genome stability in the nervous system. However, despite intense interest in the
molecular details of ATM function, its role in the nervous system remains elusive, as little is known about the
genomic lesions or key substrates that activate ATM in an in vivo neural setting. We recently showed that ATM
is critical for preventing the accumulation of Topoisomerase-1-DNA cleavage complexes (Top1cc) in the nervous
system, which can lead to DNA strand breaks. This pathogenic Topoisomerase-1-DNA lesion directly impacts
genome stability and may underpin disease etiology in A-T and other related neurodegenerative syndromes.
Our studies have also revealed that elevation of DNA damage associated with ATM loss results in transcriptional
disruption of essential cerebellar genes via the occurrence of pathogenic R-loops, a DNA/RNA intermediate that
can form during transcription. These data have lead to our hypothesis that aberrant topoisomerase activity and
causally related R-loops are etiologic genotoxins contributing to neurodegeneration in A-T and related disorders.
Many genome stability factors (including ATM) that regulate topoisomerase function or restrain R-loop formation
are linked to neurologic disease, suggesting a critical regulatory genome maintenance axis that prevents these
potentially damaging lesions from causing neurodegeneration. During the prior grant cycle we developed
multiple unique mouse models with which to interrogate ATM function, and to determine the pathogenic impact
of specific genome lesions in the nervous system. These unique mouse models are central to the experiments
proposed in this application. Amongst these is an inducible Topoisomerase-1 mutation that promotes formation
of Top1cc in the nervous system, which synergizes strongly with ATM loss to cause cerebellar dysfunction and
ataxia. This proposal will provide substantial new information to enhance our understanding of the central
mechanisms that maintain the neural genome. Moreover, data from this work will provide important groundwork
for the eventual development of therapeutic approaches to treat ne...

## Key facts

- **NIH application ID:** 9851944
- **Project number:** 5R01NS037956-21
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** PETER J MCKINNON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,656
- **Award type:** 5
- **Project period:** 1998-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851944

## Citation

> US National Institutes of Health, RePORTER application 9851944, ATM and DNA Damage in the Nervous System (5R01NS037956-21). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851944. Licensed CC0.

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