# Regulatory Enzymes and Systems in Cell Cycle Control

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $945,465

## Abstract

PROJECT SUMMARY/ABSTRACT
The proposed research explores the fascinating regulatory system that governs the eukaryotic cell division
cycle. The cell-cycle control system is based on master regulatory enzymes that include the cyclin-dependent
protein kinases (Cdks) and a ubiquitin ligase called the anaphase-promoting complex or cyclosome (APC/C).
As the cell progresses through the steps of cell division, sequential Cdk-cyclin complexes modify hundreds of
proteins, leading to chromosome duplication in S phase and alignment of duplicated chromosome on the
mitotic spindle in M phase. The APC/C then triggers destruction of several key regulators, unleashing the
dramatic events of chromosome segregation and cytokinesis. One critical APC/C substrate is securin, an
inhibitor of the protease, separase; APC/C-mediated securin destruction releases separase to cleave the
cohesin complex holding duplicated chromosomes together. The precise timing of cell cycle events requires
that Cdks and the APC/C are activated and modify their targets in a specific order. The biochemical
mechanisms underlying this order are the central focus of the research described in this application. The work
will explore a diverse array of interesting mechanistic problems in Cdk and APC/C function. Studies in budding
yeast will address the complex information processing that can be achieved through multi-site phosphorylation
of Cdk substrates, focusing on transcriptional regulators that govern cyclin gene expression. Multiple lines of
investigation will address the mechanisms by which the APC/C, together with its substrate-binding activator
subunit, controls the destruction of specific targets. A newly developed single-molecule approach will provide
rigorous quantitative measurements of APC/C-substrate interactions, providing insight into the variations in
substrate affinity that underlie the ordering of cell cycle events. Biochemical and structural approaches with
human proteins will be used to unravel the mechanisms by which the APC/C activator subunit is loaded onto
the APC/C by the chaperonin TRiC/CCT. Similar approaches will be used to determine the mechanisms by
which human separase recognizes its substrates, and the mechanisms by which securin and other regulatory
proteins inhibit separase catalytic function. The information gained from these studies will provide important
new insights into the control of cell-cycle progression, and will thereby enhance our understanding of diseases,
such as cancer, in which cell-cycle control or chromosome segregation is defective. These studies will also
illuminate general regulatory mechanisms of major importance throughout cell biology and human disease.

## Key facts

- **NIH application ID:** 10165180
- **Project number:** 2R35GM118053-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** DAVID Owen MORGAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $945,465
- **Award type:** 2
- **Project period:** 2016-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165180

## Citation

> US National Institutes of Health, RePORTER application 10165180, Regulatory Enzymes and Systems in Cell Cycle Control (2R35GM118053-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10165180. Licensed CC0.

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