# Molecular mechanisms of Werner syndrome helicase in genome stability and aging

> **NIH NIH K99** · UNIVERSITY OF TEXAS AT AUSTIN · 2022 · $108,000

## Abstract

PROJECT SUMMARY
 Progeroid syndromes mimic aging at an accelerated rate and are key to understanding both premature
and normal aging. One class of progeroid syndromes results from defective DNA repair pathways. For example,
Werner syndrome (WS)—a rare inherited disease characterized by premature aging and cancer—is caused by
mutations in the DNA repair helicase WRN. WS patients closely recapitulate many normal aging phenotypes,
making WS a model system for aging. However, the cellular and molecular mechanisms involved in WS
pathologies remain poorly understood. Here, I propose to answer critical questions regarding the functions of
WRN via an interdisciplinary approach that includes structural biology, single-molecule biochemistry, and cell
biology.
 My career goal is to establish an independent research program dedicated to understanding the
molecular and cellular mechanisms of genomic instability associated with aging and aging-related diseases. As
a first step to achieving this goal, I have pursued postdoctoral training in single-molecule microscopy and
biochemistry, complementing my background in structural biology and biophysical techniques. The mentoring
phase of the K99/R00 award will provide me with additional training in cryo-electron microscopy, cell biology,
telomere biology, and the biology of human aging through an expert group of mentors and advisors. Here I
propose to: (1) Determine the molecular architecture of full-length WRN (2) Identify how the nuclease and
helicase activities of WRN are regulated (3) Determine how WRN cooperates with telomeric proteins to unwind
G-quadruplexes during telomere replication to prevent telomere loss, and (4) determine how WRN-deficiency
leads to inflammation and premature cellular senescence. Completion of these aims will represent a major step
forward in our understanding of WRN’s role in preventing genomic instability and will lay the groundwork for my
long-term goals to determine the mechanisms of genome maintenance by other DNA repair enzymes and their
importance in human aging and age-related pathologies.
 A K99/R00 award will allow me to establish an independent research program that will make me a strong
candidate for a tenure-track position at a leading U.S. research institution. My work will provide important insights
into how WRN and its interaction partners maintain our genomes and help us understand the biological
consequences of WRN dysregulation. Furthermore, these studies will provide a more detailed understanding of
how WRN-deficiency leads to accelerated aging phenotypes found in WS.

## Key facts

- **NIH application ID:** 10322752
- **Project number:** 5K99AG066938-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Michael Soniat
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $108,000
- **Award type:** 5
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322752

## Citation

> US National Institutes of Health, RePORTER application 10322752, Molecular mechanisms of Werner syndrome helicase in genome stability and aging (5K99AG066938-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322752. Licensed CC0.

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