# Replication stress in laminopathies: causes and consequences

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2022 · $333,300

## Abstract

Abstract
The spatial organization of the genome has emerged as an additional level of regulation of genome function
and integrity. Lamins provide a scaffold for the compartmentalization of genome functions, being important for
nuclear architecture, response to mechanical stress, chromatin organization, and DNA transcription, replication
and repair. These findings, and the association of lamins mutations with degenerative disorders, premature
aging, and cancer, provide evidence for these proteins operating as “caretakers of the genome”. However, the
mechanisms whereby lamins regulate genome function and stability remain poorly understood. Unveiling these
mechanisms is key to identify therapies that ameliorate the progression of lamin-related diseases in patients.
Our proposal combines molecular, cellular, and organismal studies, to identify new mechanisms contributing to
the pathology of laminopathies, focusing on Hutchinson Gilford Progeria Syndrome (HGPS), a premature aging
disease caused by a mutant lamin A protein called “progerin”. We present evidence for lamins playing a direct
role in DNA replication. Lamins depletion reduces recruitment of factors that protect stalled forks, leading to
nuclease-mediated fork degradation, and replication stress (RS)-induced genomic instability. Progerin
expression elicits a more robust effect on DNA replication, causing replication fork stalling, in addition to fork
deprotection and degradation. RS in progerin-expressing cells is accompanied by upregulation of the cGAS/
STING cytosolic DNA sensing pathway, and activation of a STAT1-regulated IFN-like response. This response
has received much attention lately due to its involvement in malignant transformation and senescence/aging.
Importantly, treatments that ameliorate HGPS cellular phenotypes, especially calcitriol, reduces RS, represses
the IFN-like response, and increases reprogramming efficiency, a paradigm of rejuvenation.
Here, we will use new technologies such as single-molecule replication assays (DNA fibers), iPOND (Isolation
of Proteins On Nascent DNA) and electron microscopy to identify molecular mechanisms whereby lamins loss
and progerin expression hinder DNA replication (Aim 1). In addition, we will determine the cause-and-effect
relationship between RS and activation of the cGAS/STING pathway and the STAT1-regulated IFN-like
response, and the consequences of these alterations for cellular fitness (Aim 2). Moreover, we will test
whether the broad beneficial effects of calcitriol in cells in vitro translate into amelioration of phenotypes in vivo
using mouse models of laminopathies (Aim 3). If successful, our study will fill gaps in our knowledge about
mechanisms whereby lamins ensure proper DNA replication, advance laminopathies’ research by identifying
new pathways contributing to cellular and organismal deterioration, and provide evidence for the benefits of
calcitriol in preclinical models, which will serve as proof-of-concept for its utili...

## Key facts

- **NIH application ID:** 10425328
- **Project number:** 5R01AG058714-05
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Susana Gonzalo Hervas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $333,300
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425328

## Citation

> US National Institutes of Health, RePORTER application 10425328, Replication stress in laminopathies: causes and consequences (5R01AG058714-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10425328. Licensed CC0.

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