# Post-translational regulation of DNA replication origin licensing in human cells

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $418,094

## Abstract

PHOSPHOREGULATION OF DNA REPLICATION ORIGIN LICENSING IN MAMMALIAN CELLS
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:** 10093060
- **Project number:** 5R01GM102413-07
- **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:** 2021
- **Award amount:** $418,094
- **Award type:** 5
- **Project period:** 2013-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093060

## Citation

> US National Institutes of Health, RePORTER application 10093060, Post-translational regulation of DNA replication origin licensing in human cells (5R01GM102413-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093060. Licensed CC0.

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