# Defining the role of bilayer lipid composition in nuclear envelope dynamics and genome protection

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $323,214

## Abstract

PROJECT DESCRIPTION
The nuclear envelope is a subdomain of the endoplasmic reticulum (ER) that surrounds and protects the
genome. Contrary to prior dogma, the nuclear envelope is not a stable structure, but is highly dynamic in both
interphase and mitosis. Defects in nuclear envelope dynamics are common to cancer cells and to genetic
disorders caused by mutations in nuclear envelope proteins that include muscular dystrophy and progeria.
Thus, elucidating mechanisms that underlie nuclear envelope dynamics will inform on our understanding of
disease mechanisms ranging from cancer to accelerated aging. An underlying principle that drives membrane
dynamics at nearly all membrane-bound organelles is the composition of bilayer phospholipids, yet little is
known about the role of phospholipids in nuclear envelope dynamics. This proposal focuses on a distinct
regulator of phospholipid synthesis, CTDNEP1 (formerly known as Dullard), that is enriched at the nuclear
envelope and is required for nuclear envelope dynamics. CTDNEP1 and its obligate binding partner NEP1R1
are a ubiquitously conserved protein phosphatase complex that activate the phosphatidic acid phosphatase
lipin; lipin's activity is central to the de novo phospholipid synthesis. The work proposed here has two main
aims: 1) to establish the functional significance of CTDNEP1-NEP1R1 localization at the nuclear envelope in
local regulation of phospholipid synthesis and nuclear envelope dynamics and 2) to elucidate a role for nuclear
envelope lipids in protecting genome integrity by regulating mitotic nuclear envelope reformation. Completion
of these goals will elucidate a potentially significant, yet understudied role for lipid-mediated regulation of
membrane dynamics at the nuclear envelope to ensure genome protection. Aim 1 will focus on the role of a
conserved region in NEP1R1 that we discovered targets/retains CTDNEP1 in the nuclear envelope/ER in
human cells. We will identify mutants in NEP1R1 that specifically disrupt enrichment of CTDNEP1-NEP1R1 at
the nuclear envelope so that it is a more generic ER protein and assess the effects on lipid composition and
nuclear envelope dynamics. Aim 2 builds on our preliminary data that CTDNEP1 regulates nuclear envelope
reformation and prevents micronucleus formation in dividing cancer cells. These data suggest that core nuclear
envelope proteins may be regulated by specific phospholipids to form the nuclear envelope from ER-derived
membranes. We will use endogenous tags combined with conventional and super-resolution live-cell imaging
to systematically define the localization and dynamics of core nuclear envelope proteins relative to nascent
nuclear membranes during nuclear envelope reformation in wild type and ctdnep1-deficient cancer cells. In
vitro lipid binding assays will identify domains in nuclear envelope proteins that directly bind to major
phospholipids. Such studies will allow the design of mutant proteins with altered lipid binding proper...

## Key facts

- **NIH application ID:** 10113366
- **Project number:** 5R01GM131004-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shirin Bahmanyar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $323,214
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113366

## Citation

> US National Institutes of Health, RePORTER application 10113366, Defining the role of bilayer lipid composition in nuclear envelope dynamics and genome protection (5R01GM131004-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10113366. Licensed CC0.

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