Donald Fox

Overview:

Please visit www.foxlabduke.com

Research overview:
Extreme genome variation in organ development and repair.

The genome provides the blueprint for life. To achieve specialized cell or tissue function, specific genome features can be altered or exploited in extreme ways. My research program focuses on two such extreme genome variations: polyploidy and codon usage bias (defined below). In multicellular organisms with specialized organ systems, the function and regulation of these two extreme genome variations remains largely mysterious. We established accessible models where these two extreme genome variations impact cell and tissue biology.

1) Polyploidy. In numerous tissues or whole organisms, one nucleus can contain tens to thousands of genomes. Such whole genome duplication, or polyploidy, massively alters the transcriptome, proteome, and metabolome. We are only just beginning to understand the purposes of polyploidy in three crucial settings: organ development, organ repair, and ectopic polyploidy that can contribute to disease. My laboratory established accessible models of these processes using Drosophila. Our goal is to uncover fundamental functions and distinguishing regulation of polyploidy.

2) Codon usage bias. The genetic code is redundant, with 61 codons encoding 20 amino acids. Despite this redundancy, synonymous codons encoding the same amino acid occur at varying frequencies. “Rare” codons occur least often while other “common” codons occur most often. Altering codon bias across evolution affects mRNA translation and has biological consequences. The impact of codon bias on tissue-specific differentiation has been largely unexplored. In Drosophila, we discovered that the ability to express genes enriched in rare codons is a defining characteristic of at least two specific organs. We are uncovering evidence that these organs express rare codon-enriched genes to achieve cell and tissue-specific identity. We are thus well-poised to define, for the first time, the role of codon bias in tissue-specific development.

Positions:

Associate Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor in Cell Biology

Cell Biology
School of Medicine

Associate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

B.S. 2000

College of William and Mary

Ph.D. 2006

University of North Carolina - Chapel Hill

Grants:

Hypertrophy vs. Proliferation Following Tissue Injury: A Drosophila Model

Administered By
Pharmacology & Cancer Biology
Awarded By
American Heart Association
Role
Principal Investigator
Start Date
End Date

Impact of polyploidy on establishing an HIV-1 reservoir in the kidney

Administered By
Medicine, Infectious Diseases
Awarded By
University of Alabama at Birmingham
Role
Principal Investigator
Start Date
End Date

Par-4 Regulation and Function in Breast Cancer Dormancy and Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Polyploidy after tissue injury: a Drosophila model

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond.

Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected.
Authors
Clay, DE; Fox, DT
MLA Citation
Clay, Delisa E., and Donald T. Fox. “DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond.Genes (Basel), vol. 12, no. 12, Nov. 2021. Pubmed, doi:10.3390/genes12121882.
URI
https://scholars.duke.edu/individual/pub1502726
PMID
34946831
Source
pubmed
Published In
Genes
Volume
12
Published Date
DOI
10.3390/genes12121882

Distinct responses to reduplicated chromosomes require distinct Mad2 responses

Authors
Stormo, BM; Fox, DT
MLA Citation
Stormo, Benjamin M., and Donald T. Fox. “Distinct responses to reduplicated chromosomes require distinct Mad2 responses.” Elife, vol. 5, ELIFE SCIENCES PUBLICATIONS LTD, May 2016. Wos, doi:10.7754/eLife.15204.
URI
https://scholars.duke.edu/individual/pub1149402
Source
wos
Published In
Elife
Volume
5
Published Date
DOI
10.7754/eLife.15204

Conserved function of Drosophila Fancd2 monoubiquitination in response to double-strand DNA breaks.

Fanconi anemia genes play key roles in metazoan DNA damage responses, and human FA mutations cause numerous disease phenotypes. In human cells, activating monoubiquitination of the Fanconi anemia protein Fancd2 occurs following diverse DNA damage stimuli. Monoubiquitinated Fancd2 forms nuclear foci to recruit additional repair factors. Fancd2 animal models to date have focused on molecular nulls or whole gene knockdown, leaving the specific in vivo role of monoubiquitination unclear. Using a point mutant in a conserved residue, we recently linked Drosophila Fancd2 monoubiquitination to a mitosis-specific DNA double-strand break response. In this context, we used CRISPR/Cas9 to generate the first animal model of an endogenous mutation in the conserved monoubiquitination site (fancd2K595R). Here, we expand upon our characterization of fancd2K595R. We also introduce and characterize additional Drosophila tools to study fancd2, including new mutant alleles and GFP-tagged rescue transgenes. Using these new reagents, we show the impact of Drosophila Fancd2 on organismal and cell viability, as well as on repair protein localization, in the presence or absence of double-strand breaks. These findings expand our understanding of Fanconi anemia gene function in vivo and provide useful reagents for DNA repair research.
Authors
Clay, DE; Jezuit, EA; Montague, RA; Fox, DT
MLA Citation
Clay, Delisa E., et al. “Conserved function of Drosophila Fancd2 monoubiquitination in response to double-strand DNA breaks.G3 (Bethesda, Md.), vol. 12, no. 8, July 2022, p. jkac129. Epmc, doi:10.1093/g3journal/jkac129.
URI
https://scholars.duke.edu/individual/pub1521814
PMID
35595243
Source
epmc
Published In
G3 (Bethesda, Md.)
Volume
12
Published Date
Start Page
jkac129
DOI
10.1093/g3journal/jkac129

Distinct responses to rare codons in select Drosophila tissues.

Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index (taCAI), to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. We further demonstrate a role for rare codons in an evolutionarily young testis-specific gene, RpL10Aa. Optimizing RpL10Aa codons disrupts female fertility. Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology.
Authors
Allen, SR; Stewart, RK; Rogers, M; Ruiz, IJ; Cohen, E; Laederach, A; Counter, CM; Sawyer, JK; Fox, DT
MLA Citation
Allen, Scott R., et al. “Distinct responses to rare codons in select Drosophila tissues.Elife, vol. 11, May 2022. Pubmed, doi:10.7554/eLife.76893.
URI
https://scholars.duke.edu/individual/pub1520273
PMID
35522036
Source
pubmed
Published In
Elife
Volume
11
Published Date
DOI
10.7554/eLife.76893

Distinct responses to rare codons in select <i>Drosophila</i> tissues

Authors
Allen, S; Stewart, R; Rogers, M; Ruiz, IJ; Cohen, E; Laederach, A; Counter, C; Sawyer, J; Fox, D
MLA Citation
Allen, Scott, et al. “Distinct responses to rare codons in select Drosophila tissues.” BioRxiv, 6 Jan. 2022. Epmc, doi:10.1101/2022.01.06.475284.
URI
https://scholars.duke.edu/individual/pub1505843
Source
epmc
Published Date
DOI
10.1101/2022.01.06.475284

Research Areas:

Aneuploidy
Cell Cycle
Gene Dosage
Genome
Genomic Instability
Image Processing, Computer-Assisted
Microscopy, Confocal
Polyploidy
Transcriptome