# Determining the role of nuclear envelope reformation proteins in regulating the cGAS/STING innate immune response in cancer

> **NIH NIH F31** · YALE UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT:
In cancer cells, exposure of self DNA to the cytosol is driven by a variety of genomic instabilities such as
micronuclei, chromatin bridges, and nuclear ruptures. This cytosolic DNA can be recognized by cytosolic DNA
sensors such as cGAS (cyclic GMP-AMP synthase), which triggers a downstream innate immune response.
Interestingly and confoundingly, the activation of the cGAS/STING innate immune pathway can protect or
sensitize tumors to immunotherapeutic interventions depending on the specific context. Therefore, insight into
the ways in which cGAS/STING signaling is regulated in cancer can inform targeted intervention. Sources of
cytosolic DNA in cancer cells arise primarily from defects in mitosis that lead to the enclosure of chromosomes
in micronuclei that are prone to rupture. These ruptured micronuclei recruit cGAS and nuclear envelope
reformation (NER) factors—such as LEM2, CHMP7, and BAF—but it remains unknown how, or if, these NER
factors impact cGAS/STING signaling but there is emerging evidence in published and in our preliminary data
that there is potential crosstalk between cGAS/STING signaling and NER proteins. The goal of this proposal
is to provide key insights into the regulation of the innate immune response to cytosolic DNA in cancer
cells by nuclear envelope reformation factors. In order to achieve this goal, I will use transfected herring
testes (HT) DNA and transfected DNA-coated beads as models for cytosolic DNA as this can be more readily
controlled compared to the stochastic formation of micronuclei, only some of which are unstable and prone to
rupture. With this model, I will use CRISPR/Cas9 gene-editing and the auxin-inducible-degron (AID) conditional
degradation system to probe the roles of NER factors in cGAS/STING signaling in response to transfected HT
DNA and DNA beads. This proposal will address fundamental aspects of cell biology and innate immune
signaling that will shed light on immunotherapeutic targets for cancer.

## Key facts

- **NIH application ID:** 10912518
- **Project number:** 5F31CA278423-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Anthony Wayne Isenhour
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912518

## Citation

> US National Institutes of Health, RePORTER application 10912518, Determining the role of nuclear envelope reformation proteins in regulating the cGAS/STING innate immune response in cancer (5F31CA278423-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10912518. Licensed CC0.

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