# Non-apoptotic functions of caspase-2 in cell division and genomic stability

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $325,336

## Abstract

PROJECT SUMMARY/ABSTRACT
Several groups have shown a strong association between caspase-2 deficiency and accelerated tumorigenesis
in murine models of lymphoma, breast, and lung cancer. Such phenotypes are often accompanied by enhanced
cell proliferation and increased genomic instability with minimal measurable apoptotic defects. Therefore
caspase-2 appears to play a crucial role in maintaining genomic stability and may do so independent of its role
in apoptosis. To test this, this proposal will study the mechanisms of caspase-2 is activation during the DNA
damage response with a focus on the upstream caspase-2 regulator PIDD. The central hypothesis is that DNA
damage induces two distinct caspase-2 activation platforms – a cytoplasmic platform that is PIDD independent
and a nucleolar platform that requires PIDD – each providing access to distinct substrates that regulate genomic
instability by both pro-apoptotic and non-apoptotic mechanisms. This hypothesis has been formulated based on
published and preliminary data produced in the applicant’s laboratory showing that caspase-2 is activated in the
cytoplasm and in the nucleolus and that the nucleolar activation is dependent on the nucleolar phosphoprotein
nucleophosmin (NPM1) for both assembly and function. This hypothesis will be tested by pursuing two specific
aims: 1) Determine the mechanisms of caspase-2 activation in the nucleolus versus the cytosol; and 2) Identify
the relative contributions of the nucleolar and cytoplasmic complexes to downstream caspase-2 functions and
how these protect from genomic instability. Under the first aim, an already proven imaging-based method for
measuring caspase-2 activation, will be used to investigate the distinct mechanisms of differential caspase-2
activation in the nucleolus and in the cytosol. These experiments will specifically probe the roles of PIDD and
NPM1. Under the second aim, based on preliminary data that shows that caspase-2-deficient cells, proliferate
faster and accumulate more DNA damage following replication stress, the requirement of the nucleolar and
cytoplasmic complexes for apoptotic and non-apoptotic caspase-2 functions will be explored in the context of
apoptosis, cell cycle regulation, substrate cleavage and DNA repair mechanisms. The approach is innovative
because it utilizes novel imaging-based techniques that are designed to assess caspase-2 activation in single
cells so that the relationship between the localization of caspase-2 activation with apoptosis, DNA damage, and
cell division will be directly explored on a per cell basis. It also provides a new paradigm of caspase activation in
the nucleolus. The proposed research is significant because it is proposed that site-specific activation of
caspase-2 in the cytosol and nucleolus governs distinct functions of this protease that cooperate to protect from
genomic instability. These mechanisms may underlie the known physiological roles of caspase-2 in tumor
suppression and in prot...

## Key facts

- **NIH application ID:** 9923704
- **Project number:** 5R01GM121389-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lisa Bouchier-Hayes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,336
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923704

## Citation

> US National Institutes of Health, RePORTER application 9923704, Non-apoptotic functions of caspase-2 in cell division and genomic stability (5R01GM121389-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9923704. Licensed CC0.

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