# Lamin A and the Fidelity of DNA Double-Strand Break Repair

> **NIH NIH R03** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $74,500

## Abstract

Project Summary
 Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal autosomal dominant genetic condition
characterized by many characteristics of accelerated aging in children. Children with HGPS die at an average
age of fourteen, usually from heart disease. It has been known for some time that the syndrome is most
commonly caused by a specific point mutation in the LMNA gene which normally codes for lamin A and its
splice variant lamin C. The LMNA mutation commonly associated with HGPS leads to increased usage of a
cryptic splice site which leads to the production of a truncated, farnesylated form of lamin A referred to as
"progerin." Quite interestingly, progerin is expressed at very low levels in healthy individuals and appears to
play a role in the normal aging process.
 Lamin A normally serves as an important component of the nuclear lamina, a structure that provides
mechanical support for the nucleus and regulates several critical cellular processes including a number of DNA
repair pathways. In HGPS, the impact of overexpression of progerin on nuclear architecture and genomic
stability is profound. One reported consequence of progerin expression is an accumulation of DNA double-
strand breaks (DSBs). To our knowledge, however, the effect that expression of progerin or other mutated
forms of lamin A has on the precise manner in which a DSB is repaired in the human genome has never been
investigated in detail. This gap in our knowledge is significant since corruption of DNA repair is commonly
viewed as playing a key role in the aging process.
 Over the past two decades, we have developed and productively used a model system for studying DSB
repair, homologous recombination, and related DNA transactions in the chromosomes of human cells. We
have engineered DNA constructs containing a mutated selectable marker gene and a closely linked sequence
that can restore function to the marker through recombination. Constructs are stably transfected into cell lines
of interest. A DSB can be introduced into the marker gene by transient expression of endonuclease I-SceI and
so we can recover a variety of DSB repair events that restore marker function by applying genetic selection.
 We will apply our system to compare and contrast DSB repair events in normal cells versus cells that
overexpress progerin or express a related variant form of lamin A. Our work will be the first in-depth
investigation into how expression of progerin impacts DSB repair pathway choice as well as the nature of
individual repair events at the nucleotide level. We will focus on the questions of whether expression of
progerin reduces the stringency of recombinational repair, enabling genetic exchange between imperfectly
matched sequences, and whether progerin inhibits precise joining of DNA ends. Either of these potential
impacts of progerin expression would likely destabilize the genome. Our studies will provide novel information
about the aging process, information that wi...

## Key facts

- **NIH application ID:** 9976012
- **Project number:** 1R03AG064525-01A1
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Alan S. Waldman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $74,500
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976012

## Citation

> US National Institutes of Health, RePORTER application 9976012, Lamin A and the Fidelity of DNA Double-Strand Break Repair (1R03AG064525-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9976012. Licensed CC0.

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