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

Publications:

Persistent DNA Repair Signaling and DNA Polymerase Theta Promote Broken Chromosome Segregation

<jats:title>Abstract</jats:title><jats:p>Cycling cells must respond to double-strand breaks (DSBs) to avoid genome instability. Mis-segregation of chromosomes with DSBs during mitosis results in micronuclei, aberrant structures linked to disease. How cells respond to DSBs during mitosis is incompletely understood. We previously showed that <jats:italic>Drosophila</jats:italic> papillar cells lack DSB checkpoints (as observed in many cancer cells). Here, we show that papillar cells still recruit early-acting repair machinery (Mre11 and RPA3) to DSBs. This machinery persists as foci on DSBs as cells enter mitosis. Repair foci are resolved in a step-wise manner during mitosis. Repair signaling kinetics at DSBs depends on both monoubiquitination of the Fanconi Anemia (FA) protein Fancd2 and the alternative end-joining protein DNA Polymerase Theta. Disruption of either or both of these factors causes micronuclei after DNA damage, which disrupts intestinal organogenesis. This study reveals a mechanism for how cells with inactive DSB checkpoints can respond to DNA damage that persists into mitosis.</jats:p><jats:sec><jats:title>Summary</jats:title><jats:p>Clay et. al. show that cells with DNA breaks that persist into mitosis activate sustained DNA repair signaling, regulated by Fanconi Anemia proteins and the alternative end-joining repair protein DNA Polymerase Theta. This signaling enables broken chromosome segregation and prevents micronuclei.</jats:p></jats:sec>
Authors
Clay, DE; Bretscher, HS; Jezuit, EA; Bush, KB; Fox, DT
MLA Citation
Clay, Delisa E., et al. Persistent DNA Repair Signaling and DNA Polymerase Theta Promote Broken Chromosome Segregation. Cold Spring Harbor Laboratory. Crossref, doi:10.1101/2021.06.18.449048.
URI
https://scholars.duke.edu/individual/pub1485778
Source
crossref
DOI
10.1101/2021.06.18.449048

Persistent DNA damage signaling and DNA polymerase theta promote broken chromosome segregation.

Cycling cells must respond to DNA double-strand breaks (DSBs) to avoid genome instability. Missegregation of chromosomes with DSBs during mitosis results in micronuclei, aberrant structures linked to disease. How cells respond to DSBs during mitosis is incompletely understood. We previously showed that Drosophilamelanogaster papillar cells lack DSB checkpoints (as observed in many cancer cells). Here, we show that papillar cells still recruit early acting repair machinery (Mre11 and RPA3) and the Fanconi anemia (FA) protein Fancd2 to DSBs. These proteins persist as foci on DSBs as cells enter mitosis. Repair foci are resolved in a stepwise manner during mitosis. DSB repair kinetics depends on both monoubiquitination of Fancd2 and the alternative end-joining protein DNA polymerase θ. Disruption of either or both of these factors causes micronuclei after DNA damage, which disrupts intestinal organogenesis. This study reveals a mechanism for how cells with inactive DSB checkpoints can respond to DNA damage that persists into mitosis.
Authors
Clay, DE; Bretscher, HS; Jezuit, EA; Bush, KB; Fox, DT
MLA Citation
Clay, Delisa E., et al. “Persistent DNA damage signaling and DNA polymerase theta promote broken chromosome segregation.J Cell Biol, vol. 220, no. 12, Dec. 2021. Pubmed, doi:10.1083/jcb.202106116.
URI
https://scholars.duke.edu/individual/pub1498224
PMID
34613334
Source
pubmed
Published In
The Journal of Cell Biology
Volume
220
Published Date
DOI
10.1083/jcb.202106116

Accelerated cell cycles enable organ regeneration under developmental time constraints in the Drosophila hindgut.

Individual organ development must be temporally coordinated with development of the rest of the organism. As a result, cell division cycles in a developing organ occur on a relatively fixed timescale. Despite this, many developing organs can regenerate cells lost to injury. How organs regenerate within the time constraints of organism development remains unclear. Here, we show that the developing Drosophila hindgut regenerates by accelerating the mitotic cell cycle. This process is achieved by decreasing G1 length and requires the JAK/STAT ligand unpaired-3. Mitotic capacity is then terminated by the steroid hormone ecdysone receptor and the Sox transcription factor Dichaete. These two factors converge on regulation of a hindgut-specific enhancer of fizzy-related, a negative regulator of mitotic cyclins. Our findings reveal how the cell-cycle machinery and cytokine signaling can be adapted to accomplish developmental organ regeneration.
Authors
Cohen, E; Peterson, NG; Sawyer, JK; Fox, DT
MLA Citation
Cohen, Erez, et al. “Accelerated cell cycles enable organ regeneration under developmental time constraints in the Drosophila hindgut.Dev Cell, vol. 56, no. 14, July 2021, pp. 2059-2072.e3. Pubmed, doi:10.1016/j.devcel.2021.04.029.
URI
https://scholars.duke.edu/individual/pub1482985
PMID
34019841
Source
pubmed
Published In
Dev Cell
Volume
56
Published Date
Start Page
2059
End Page
2072.e3
DOI
10.1016/j.devcel.2021.04.029

Communal living: the role of polyploidy and syncytia in tissue biology.

Multicellular organisms are composed of tissues with diverse cell sizes. Whether a tissue primarily consists of numerous, small cells as opposed to fewer, large cells can impact tissue development and function. The addition of nuclear genome copies within a common cytoplasm is a recurring strategy to manipulate cellular size within a tissue. Cells with more than two genomes can exist transiently, such as in developing germlines or embryos, or can be part of mature somatic tissues. Such nuclear collectives span multiple levels of organization, from mononuclear or binuclear polyploid cells to highly multinucleate structures known as syncytia. Here, we review the diversity of polyploid and syncytial tissues found throughout nature. We summarize current literature concerning tissue construction through syncytia and/or polyploidy and speculate why one or both strategies are advantageous.
Authors
Peterson, NG; Fox, DT
MLA Citation
Peterson, Nora G., and Donald T. Fox. “Communal living: the role of polyploidy and syncytia in tissue biology.Chromosome Res, June 2021. Pubmed, doi:10.1007/s10577-021-09664-3.
URI
https://scholars.duke.edu/individual/pub1484521
PMID
34075512
Source
pubmed
Published In
Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology
Published Date
DOI
10.1007/s10577-021-09664-3

Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo.

Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. Here, by altering codon usage as a novel platform to control signaling output, we screened the Drosophila genome for modifiers specific to either weak or strong Ras-driven eye phenotypes. Our screen enriched for regions of the genome not previously connected with Ras phenotypic modification. We mapped the underlying gene from one modifier to the ribosomal gene RpS21. In multiple contexts, we show that RpS21 preferentially influences weak Ras/MAPK signaling outputs. These data show that codon usage manipulation can identify new, output-specific signaling regulators, and identify RpS21 as an in vivo Ras/MAPK phenotypic regulator.
Authors
Sawyer, JK; Kabiri, Z; Montague, RA; Allen, SR; Stewart, R; Paramore, SV; Cohen, E; Zaribafzadeh, H; Counter, CM; Fox, DT
MLA Citation
Sawyer, Jessica K., et al. “Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo.Plos Genet, vol. 16, no. 12, Dec. 2020, p. e1009228. Pubmed, doi:10.1371/journal.pgen.1009228.
URI
https://scholars.duke.edu/individual/pub1468626
PMID
33296356
Source
pubmed
Published In
Plos Genet
Volume
16
Published Date
Start Page
e1009228
DOI
10.1371/journal.pgen.1009228

Research Areas:

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