# Cell Cycle Dynamics that Ensure Genome Maintenance

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $86,365

## Abstract

CELL CYCLE CONTROLS THAT ENSURE GENOME MAINTENANCE (COOK)
SUMMARY
 Our research program seeks insight into the fundamental architecture and regulation of the
human cell division cycle, with specific focus on DNA replication competence. Complete and
efficient duplication of an entire mammalian genome requires that many thousands of DNA
replication origins become licensed in G1 phase through the DNA loading of MCM helicase
complexes. Loaded MCM complexes render genomic loci competent for replication initiation
during S phase. Loss of normal origin licensing control causes genome instability, which can
cause oncogenesis, developmental defects, and degeneration. Origin licensing control is as
important for ensuring normal genome maintenance as companion mechanisms such as
replication fork control and stability or DNA repair, but the regulation of origin licensing is only
partly understood. For example, how is complete origin licensing achieved in cells with
dramatically different G1 lengths, such as during development or after oncogene activation?
How is origin licensing activity distributed in a heterogenous chromatin environment? How is
origin licensing controlled during transitions into and out of the cell cycle? These unanswered
questions preclude the comprehensive understanding of proliferation control needed to
diagnose and treat pathologies in which cell proliferation is a hallmark.
 Our long-term goal is to understand how DNA replication origin licensing is governed by
intracellular and extracellular pathways that control proliferation and development and to
understand the outcomes of perturbations to those controls. Our current and future projects are
organized into scientific questions clustered into two central goals: Goal 1) Define how MCM
loading dynamics regulate G1 progression, Goal 2) Determine the molecular events that
establish and maintain cell cycle exit to quiescence. In recent years, we developed innovative
experimental tools and approaches using quantitative live cell and fixed single cell analyses in
cultured human cells. We combine these tools with molecular genetics and biochemistry. We
focus on uncovering molecular mechanisms and their inter-relationships, and then test the
consequences of perturbing those mechanisms. Our prior efforts produced a consistent stream
of basic scientific discoveries and advances for both the field and the scientific workforce. The
impacts of success towards our central goals are to define previously unexplored mechanisms
in the mammalian cell cycle and to probe the dynamics of molecular events required for genome
maintenance.

## Key facts

- **NIH application ID:** 10426557
- **Project number:** 3R35GM141833-01S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jeanette Gowen Cook
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $86,365
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426557

## Citation

> US National Institutes of Health, RePORTER application 10426557, Cell Cycle Dynamics that Ensure Genome Maintenance (3R35GM141833-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10426557. Licensed CC0.

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