# Diversity Supplement: Post-Translational Regulation of DNA Replication Origin Licensing in Human Cells

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $79,827

## Abstract

This proposal seeks new insight into the fundamental organization of the human cell division cycle
and how perturbations to that organization lead to genome instability and pathological states.
Complete and efficient duplication of the entire human genome requires that many thousands of
DNA replication origins become “licensed” in G1 of each cell division cycle through the loading of
MCM helicase complexes. DNA-loaded MCM complexes are then activated during S phase. Loss
of normal origin licensing control causes hypersensitivity to replication stress and induces genome
instability, which can ultimately lead to oncogenesis, developmental defects, and degeneration.
Our long-term goal is to understand how DNA replication origin licensing control is coordinated
with intracellular and extracellular signaling pathways that control proliferation and development.
We hypothesize that perturbations to this coordination cause genome instability and proliferation
failure. Our experimental approach is a combination of quantitative single cell analyses with
molecular biology and biochemistry using cultured human cells. We focus on uncovering
molecular mechanisms and dynamics, and then testing the cellular consequences of disrupting
those mechanisms. Our recent progress, innovative experimental strategies, and preliminary data
inspire a new series of projects to address these specific goals: 1) determine precisely how
changes in individual cyclin/CDK enzymes impact origin licensing and the G1 to S phase transition
2) define the molecular consequences phosphorylating an essential origin licensing protein, Cdt1,
and 3) define the relationships among CDK-mediated phosphorylation, the APC/C E3 ubiquitin
ligase, and origin licensing, particularly for regulation of the Cdc6 licensing protein and preventing
re-replication. Success will shed light on the mechanisms that can drive mutagenesis, cancer, cell
death, and aging. The deep understanding of cell proliferation control sought through the pursuit
of these aims will have downstream implications for efforts to precisely define and treat human
disease and for future regenerative therapies.

## Key facts

- **NIH application ID:** 10120875
- **Project number:** 3R01GM102413-06S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jeanette Gowen Cook
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $79,827
- **Award type:** 3
- **Project period:** 2013-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120875

## Citation

> US National Institutes of Health, RePORTER application 10120875, Diversity Supplement: Post-Translational Regulation of DNA Replication Origin Licensing in Human Cells (3R01GM102413-06S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10120875. Licensed CC0.

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