# The Role of LEM Domain Proteins in Nuclear Function

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $385,262

## Abstract

ABSTRACT
Human laminopathies are caused by mutations in genes encoding nuclear lamina (NL)
proteins. These proteins form an extensive network that lies beneath the inner nuclear
membrane. 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 conserved double stranded DNA
and histone binding protein. Interactions between LEM-D proteins and BAF target
nuclear membranes to chromosomes during nuclear assembly after mitosis. In addition,
LEM-D proteins interact with BAF to tether the genome to the nuclear periphery and
establish repressed chromatin domains in non-dividing cells. 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. We expect our studies will have a broad
impact. 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:** 10189633
- **Project number:** 5R01GM087341-07
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** PAMELA K. GEYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,262
- **Award type:** 5
- **Project period:** 2010-06-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189633

## Citation

> US National Institutes of Health, RePORTER application 10189633, The Role of LEM Domain Proteins in Nuclear Function (5R01GM087341-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189633. Licensed CC0.

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