# Death and Destruction: How the Ubiquitin Proteasome System Executes Linker Cell-type Death

> **NIH NIH F32** · ROCKEFELLER UNIVERSITY · 2022 · $67,582

## Abstract

Project Summary
The long-term goal of the proposed research is to understand the cell biological mechanisms that
execute non-apoptotic cell death. Programmed cell death is essential for organismal development and
homeostasis, and its disruption is associated with many human diseases including cancer and
neurodegeneration. Apoptosis is a prominent cell death form, however mutations in key apoptotic regulators only
cause minor developmental defects. Non-apoptotic programs, therefore, also exist, but their molecular basis is
poorly understood. Linker Cell-type Death (LCD) is a non-apoptotic and caspase-independent cell death process
operating in C. elegans development, and its morphological hallmarks have also been observed in vertebrate
development and disease. The Ubiquitin Proteasome System (UPS) is a key effector of LCD in C. elegans, but
how it executes cell death is unknown. Here I will use powerful genetic and molecular tools in C. elegans
to identify and characterize the proteolytic targets of the UPS during LCD and determine how their
degradation trigger cell demise. In contrast to apoptosis, which uses caspases that transiently bind their
substrates and, remarkably, remain poorly understood, the UPS stably interacts with its substrates. Therefore,
the proteins I discover that precipitate cell death may unearth general mechanisms of cellular destruction that
also function during apoptosis and disease. Indeed, our preliminary data suggest that one candidate substrate
degraded by the UPS is an enzyme required for the maintenance of heterochromatin, which is in line with our
previous observations that dying linker cells exhibit an open chromatin state. Therefore, this proposal will
investigate the exciting hypothesis that chromatin remodeling, precipitated by the UPS, triggers cellular
destruction. I will also discover additional proteolytic targets and mechanisms that execute non-apoptotic cell
death with yeast 2-hybrid and RNAi screens. Because dysregulation of the UPS and chromatin state are also
linked to tumorigenesis and neurodegenerative diseases, my studies can provide greater understanding of cell
death programs disrupted in disease that can point towards new therapeutic targets.

## Key facts

- **NIH application ID:** 10464485
- **Project number:** 1F32GM145036-01A1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Lauren Bayer Horowitz
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 1
- **Project period:** 2022-09-28 → 2024-09-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464485

## Citation

> US National Institutes of Health, RePORTER application 10464485, Death and Destruction: How the Ubiquitin Proteasome System Executes Linker Cell-type Death (1F32GM145036-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464485. Licensed CC0.

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