# Cell cycle and checkpoint variations in development and disease

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $489,267

## Abstract

Project Summary
The Calvi lab investigates the regulation of cell cycle and genome integrity using Drosophila melanogaster as a
model system. Our ongoing studies are defining the variations in cell cycle and checkpoints in development
and how these variations are related to disease. One cell cycle variant that we have focused on is called the
endocycle, which is a G / S cycle without division that results in large, polyploid cells. The endocycle is a
normal variant growth program in a variety of tissues and organisms including humans. In recent years, it has
become increasingly clear that mitotically dividing cells can also switch to polyploid endocycles in response to
conditional inputs. We call these induced endocycling cells (iECs) to distinguish them from the developmental
endocycling cells (devECs) that contribute to the growth of specific tissues during development. While iECs
can be beneficial for tissue regeneration, they also can contribute to tissue malformations and cancer. We had
previously shown that both devECs and iECs repress the p53 apoptotic response to DNA damage, and that
iECs in both Drosophila and human cell culture can return to an error prone mitosis that compromises genome
integrity. Our evidence, together with that from other labs and the clinic, has led to a prevailing model that the
survival and division of cancer iECs contributes to cancer therapy resistance and relapse. Nevertheless, much
remains unknown about the mechanisms that regulate iEC cycling, growth, and checkpoint responses and
what global impact these properties have on tissue malformations and tumorigenesis. We are continuing to
address these questions using Drosophila as a model system to study iECs in vivo. This has led to a
fundamentally new viewpoint that iECs are not just a switch in cell cycle, but also represent a distinct cell state
with modified growth, stress response, and signaling pathways that have both cell autonomous and
nonautonomous effects on tissue growth. We are using integrated cell, molecular and genomic approach to
further define this cell state and uncover new mechanisms by which it affects tissue growth and oncogenesis.
As part of this inquiry, we continue to define how proapoptotic p53 target genes are repressed in endocycling
cells to discover conserved mechanisms that couple apoptotic competence to cell cycle programs. These
ongoing studies into the p53 pathway have led us to discover that different Drosophila p53 protein isoforms
have overlapping and distinct functions in multiple cell types and processes. We are investigating how these
p53 functions are regulated by its localization to subnuclear bodies, a process that is conserved with human
p53. Altogether, it is anticipated that the outcomes of our investigations will uncover new cellular and molecular
mechanisms that regulate growth and stress response, which will ultimately lead to the better diagnosis and
treatment of developmental malformations and cancer.

## Key facts

- **NIH application ID:** 10765262
- **Project number:** 1R35GM152255-01
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** BRIAN R CALVI
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $489,267
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765262

## Citation

> US National Institutes of Health, RePORTER application 10765262, Cell cycle and checkpoint variations in development and disease (1R35GM152255-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765262. Licensed CC0.

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