# Genome-wide dysregulation of R-loops in Ataxia Telangiectasia neurological pathogenesis

> **NIH NIH F31** · EMORY UNIVERSITY · 2024 · $48,974

## Abstract

Project Abstract:
Ataxia Telangiectasia (AT), a multisystemic neurodegenerative disease characterized by decreasing motor
coordination, mental development, immune defects, and telangiectasia of the eyes, affects up to 1 in 40,000 to
100,000 people worldwide. A recessive early childhood onset disorder, AT is caused by mutations within the
ataxia telangiectasia mutated (ATM) threonine/serine kinase which plays crucial roles within the DNA damage
response (DDR). However, the precise molecular mechanisms underlying AT pathogenesis and how ATM loss-
of-function leads to deficient DDR remain elusive. R-loops, three stranded RNA-DNA structures composed of an
DNA-RNA hybrid and a non-template DNA strand, have emerged as key components of double strand break
(DSB)-induced DDR. Mounting evidence has documented critical roles of R-loops in both causing and
responding to DSBs. As DSBs and the failure of their repair play major roles in the pathology of AT, R-loop
dysregulation is likely to contribute to AT pathogenesis. One recently identified kinase substrate of ATM is
methyltransferase like 3 (METTL3) protein, a N6-methyladenosine (m6A) methyltransferase. m6A on the RNA
strand of R-loops is present inside nuclei and affects R-loop formation during DSB repair. The relationship
between ATM-METTL3 phosphorylation in response to DNA damage and regulation of R-loop formation, which
could play crucial roles in AT pathogenesis, has yet to be defined. Our preliminary data has demonstrated a
global trend of R-loops decreasing in AT patient-derived neurons compared to healthy controls. ~20% of these
lost loci were rescued in an isogenic line where the ATM mutation had been corrected. We hypothesize that in
AT, the lack of METTL3 phosphorylation by ATM could globally dysregulate R-loop formation and underly AT
progression. In Aim 1 we will investigate the global landscape of R-loops and analyze their effect on gene
expression and chromatin accessibility throughout neuronal differentiation in healthy, AT-derived, and isogenic
neurons. In Aim 2, we will define how ATM-mediated phosphorylation of METTL3 impacts the formation of R-
loops. We will generate iPSC-derived motor neurons from age-matched healthy controls, AT patients, and their
isogenic lines with the pathogenic mutations corrected by genome editing to systematically identify critical R-
loop loci that are associated with AT and mechanistically explore the role of ATM truncations in AT progression
through METTL3-dependent R-loop regulation.

## Key facts

- **NIH application ID:** 10836345
- **Project number:** 5F31NS127537-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Katherine R. Westover
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-03-13 → 2026-01-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836345

## Citation

> US National Institutes of Health, RePORTER application 10836345, Genome-wide dysregulation of R-loops in Ataxia Telangiectasia neurological pathogenesis (5F31NS127537-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10836345. Licensed CC0.

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