# The Role of LEM Domain Proteins in Nuclear Function

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $148,140

## Abstract

Project Summary
Human laminopathies are caused by mutations in genes encoding nuclear lamina (NL) proteins.
A unifying disease model suggests that lost tissue homeostasis is due to a failure to maintain
adult stem cells. Although NL proteins responsible for laminopathies have been identified, it
remains unclear how these proteins maintain healthy stem cell populations and promote
tissue homeostasis. The conserved NL family of LEM-domain (LEM-D) proteins play a critical
role in building nuclear structure and the NL. LEM-D proteins bind Barrier-to-Autointegration
Factor (BAF), a double stranded DNA and histone binding protein. We investigate the Drosophila
LEM-D family, focusing on Otefin, a LEM-D protein that is required for survival of adult germline
stem cells (GSCs). The otefin mutant GSCs carry structural deformities of the NL and chromatin
changes that are shared with laminopathic cells. My lab discovered that these mutant GSCs die
because of activation of a novel checkpoint pathway that uses two DNA damage response
(DDR) kinases, ATR and Checkpoint kinase 2 (Chk2). Although otefin mutant GSCs carry DNA
damage, damage accumulation depends upon Chk2, demonstrating that DNA damage results
from checkpoint activation. Based on these and other data, we hypothesize that NL deformation
is responsible for activation of ATR and Chk2, a prediction supported by emerging evidence that
ATR is a global sensor of structural deformities of cellular components. In this proposal, two
Aims are proposed. In Aim 1, we will define the mechanism of ATR/Chk2 activation in otefin
mutant GSCs. In Aim 2, we define Chk2-dependent pathways involved in GSC death. Nuclear
shape changes are shared features of laminopathies and premature aging syndromes. We
predict that activation of the NL checkpoint might contribute to lost stem cell maintenance in
these diseases.

## Key facts

- **NIH application ID:** 10175883
- **Project number:** 3R01GM087341-06S1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** PAMELA K. GEYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $148,140
- **Award type:** 3
- **Project period:** 2010-06-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10175883

## Citation

> US National Institutes of Health, RePORTER application 10175883, The Role of LEM Domain Proteins in Nuclear Function (3R01GM087341-06S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10175883. Licensed CC0.

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