# SCF Ubiquitin Ligases in Cell Cycle Control and Chromosome Stability

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $314,382

## Abstract

PROJECT SUMMARY ABSTRACT
Dynamic oscillations in the abundance and activity of key proteins drives cell cycle progression. This is typified
by cyclins and cyclin kinase inhibitors (CKIs), which oscillate during cell cycle progression and determine the
activation kinetics of Cyclin Dependent Kinases, which propel the cell cycle forward. Defining the pathways,
networks and mechanisms underlying dynamics in protein abundance during normal cell cycles is essential to
understanding proliferative control. Ubiquitin is the major regulator of protein degradation in eukaryotes and
plays an essential and highly conserved role in cell cycle progression. The Skp1-Cul1-F-box (SCF) family of E3
ubiquitin ligases are major regulators of cell cycle progression and sculpt the protein landscape post-
translationally to facilitate proliferation. SCF ligases engage a set of ~70 interchangeable substrate receptors
termed F-box proteins, which dictate SCF target selection. The eponymous Cyclin F is the founding member of
the F-box family and has a cyclin homology domain like that found in the canonical CDK activators. Rather
than activate a CDK to promote cell cycle via phosphorylation, cyclin F binds to the SCF, promoting cell cycle
through ubiquitination. Cyclin F mRNA and protein levels oscillate significantly during the cell cycle and to a
greater extent than other F-box encoding genes. Cyclin F is required for viability in mice and essential for
growth/survival in many human cell lines. Further, it is overexpressed in cancer, and its mutation is linked to
the neurodegenerative disease amyotrophic lateral sclerosis. Nevertheless, there remain significant knowledge
gaps related to what pathways cyclin F controls and how it is regulated. Defining substrates and mechanisms
of cyclin F is significant to a fundamental understanding of cell cycle, as well as human health. During the
previous funding cycle, our lab identified several cyclin F substrates, highlighting its importance in cell cycle
control. Here, we build on that work, defining a new substrate with important roles in normal cell cycle control
and with relevance to disease, while also beginning to dissect the complex mechanisms by which cyclin F is
controlled. Borne out of innovative, unbiased, computational, and proteomic strategies, our data suggest new,
critical roles for cyclin F in cell cycle, and undescribed mechanisms underlying its regulation. In aim 1, we
examine the role of cyclin F in G1/S progression through regulation of a tumor suppressor in the
retinoblastoma (RB)-pocket protein family, RBL2/p130. We will determine the mechanisms by which cyclin F
controls the RB-pathway and how this contributes to gene expression, cell cycle, and proliferative control. In
aims 2 and 3, we turn our attention towards mechanisms that converge on cyclin F to regulate its abundance
and potentially activity. Aim 2 is focused on the regulation of cyclin F by kinases and how they determine cyclin
F stability. In aim ...

## Key facts

- **NIH application ID:** 10365189
- **Project number:** 2R01GM120309-06
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Michael James Emanuele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $314,382
- **Award type:** 2
- **Project period:** 2016-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365189

## Citation

> US National Institutes of Health, RePORTER application 10365189, SCF Ubiquitin Ligases in Cell Cycle Control and Chromosome Stability (2R01GM120309-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10365189. Licensed CC0.

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