# Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $418,448

## Abstract

ABSTRACT
DNA damage-mediated genome instability is a contributing factor in the causation of human diseases, including
neurodegeneration, immunological disorders, and cancer. Understanding how cells prevent and manage DNA
damage is highly significant. R loop, a transcription-linked 3 nucleic-acid structure consisting of a RNA:DNA
hybrid and a displaced single-strand DNA (ssDNA), when decorated with histone H3S10p mark causes genomic
instability upon its cleavage into DNA double strand breaks (DSBs). Currently, nothing is known about R loop
dysfunction in the causation of human primary immunodeficiency disorders (PIDDs), aka, inborn errors of
immunity. Using a PID disease model of human Wiskott-Aldrich syndrome (WAS), we recently discovered an
essential nuclear role of WASp, the protein deficient in WAS, in limiting R loop-mediated DNA damage in CD4+
T helper 1 (Th1) lymphocytes. This discovery has opened up a new avenue of research into how WASp, a
nucleocytoplasmic protein with dual-roles in F-actin polymerization and gene transcription, ensures R loop-linked
genome stability. The current proposal seeks to define the nuclear signaling pathways and mechanisms involved
in ensuring a healthy R loop balance, and therefore a stable genome, in human Th cells, and how their
disruptions by WAS gene mutations is causally-linked to the development of immune deficiency and clinical
phenotypes in WAS. Aim 1 focuses on defining chromatin-based mechanisms by which WASp influences the
balance between beneficial (“good”) R loops and deleterious (“bad”) R loops, and their effects in the causation
of WAS Th1 and WAS Th2 cellular phenotypes. Aim 2 will clarify the mechanism of the newly identified mRNA
splicing defect in WAS Th cells as it relates to R loop formation and genome instability. Aim 3 will utilize primary
T cells from multiple WAS patients of differing clinical severities to establish R loop load in the T cells as a
“dynamic” disease biomarker, and to define the involvement of nuclear-F-actin effects of WASp in WAS
phenotype development. In the long-term, the knowledge gained from these studies will foster the development
of novel prognostics, diagnostics, and therapeutics for this PID and other R loop-mediated immunological
disorders.

## Key facts

- **NIH application ID:** 10102190
- **Project number:** 5R01AI146380-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** YATIN M VYAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,448
- **Award type:** 5
- **Project period:** 2020-02-07 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102190

## Citation

> US National Institutes of Health, RePORTER application 10102190, Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome (5R01AI146380-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102190. Licensed CC0.

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