Rafal Donczew, Ph.D.

During gene transcription, cells read DNA instructions to begin production of proteins that do most of the work in a cell. Every cell division involves duplication of the genetic material in a process called DNA replication. Mistakes during transcription and DNA replication are a common cause of human diseases, including cancer. Our lab studies the complex mechanisms that regulate these processes. Understanding the details of these mechanisms creates opportunities for targeted drug development.

In many organisms, including both simple unicellular yeast and humans, DNA is stored as chromatin, which consists of a DNA strand wrapped around a bead-like structure made of proteins called histones. Many proteins involved in transcription can “read” specific modifications on histones that are deposited and erased by other specialized factors.

Our studies focus on chromatin readers from a family of proteins called BET which are involved in the regulation of transcription. Recent findings suggest the same proteins affect DNA replication. BET proteins are potential drug targets for many types of cancer and immunoinflammatory conditions, but their regulation and roles are poorly understood.

Yeast cells are an excellent model used to understand the functions of human cells. In prior work, we found that yeast BET proteins and their human equivalents have similar roles. Now, we use yeast and other models to investigate fundamental mechanisms of transcription and DNA replication to pave a way for development of new therapies for human diseases.

Genomic DNA is a shared substrate for the two principal processes in the cell nucleus – gene transcription and DNA replication. In our lab, we study the fundamental mechanisms of transcription and DNA replication in eukaryotes. We aim to understand what aspects of the regulation of transcription and DNA replication differentiate healthy and diseased cells. Ultimately, we hope to reveal specific dependencies, thus paving the way for the development of new targeted therapies. To achieve these goals, our lab utilizes many approaches including functional genomics, proteomics, biochemistry, and molecular biology. Conservancy of factors and pathways involved in transcription and DNA replication allows us to use the powerful yeast system as our primary model.

Recruitment, regulation, and roles of chromatin readers from the BET family
We previously characterized yeast bromodomain-containing factors Bdf1/2 as functional homologues of chromatin readers from the human BET family. Aberrant activity of human BET proteins in transcriptional regulation have been linked with the development and progression of many diseases. Canonical models assert that, as chromatin readers, BET proteins are recruited to regulatory elements by their tandem bromodomains, which ‘read’ acetylated chromatin. However, it is less clear how BET proteins regulate transcription once recruited, and recent evidence suggests that bromodomain activity alone does not fully explain recruitment. For example, diseased cells quickly develop resistance to therapeutics that specifically inhibit bromodomain activity.

Further complicating the subject, our recent unpublished findings have implicated BET proteins in the regulation of DNA replication. Based on this background, we are now exploring the roles of BET proteins in both transcription and DNA replication. We are investigating the BET protein interaction network, functional crosstalk between BET proteins and coactivators and chromatin-modifying complexes, mechanisms of BET protein recruitment to chromatin, specific functions of conserved domains of BET proteins, and the level of a functional redundancy between distinct members of the BET family. The last project involves both yeast and mammalian cells as models.

Spatiotemporal coordination of gene transcription and DNA replication
The maintenance of cellular homeostasis and genome stability depends on the strict control of gene transcription and DNA replication and the spatiotemporal coordination of the two processes to avoid conflicts. A plausible model asserts that transcription and DNA replication are coordinated at the early stages of both processes when respective machineries are assembled and activated. In support of this model, most genes are transcribed during the whole cell cycle, ~50% of origins of replication are located in active gene promoters or promoter-proximal regions, transcriptionally active genes tend to be replicated earlier, and both initiation of transcription and initiation of DNA replication are positively associated with the same chromatin characteristics.

Based on this background and our unpublished findings, we are testing a model where BET proteins function as a direct link between genome-wide regulation of transcription and DNA replication. Our preliminary data indicate that BET proteins may facilitate the crosstalk between transcription and DNA replication at least partially through the recruitment of distinct protein complexes involved in chromatin dynamics. We are also testing if replication initiation factors directly contribute to the regulation of transcription when cells prepare for DNA replication.

Education
M.S., Wrocław University of Science and Technology, Poland, 2009
Ph.D., Hirszfeld Institute of Immunology and Experimental Therapy, Poland, 2015
Postdoctoral Scholar, Fred Hutchinson Cancer Research Center, Seattle, Washington, 2015-2022

Honors and Awards
PRELUDIUM pre-doctoral grant, National Science Center, Poland, 2013-2015
START Scholarship, Foundation for Polish Science, Poland, 2015
EMBO Postdoctoral Fellowship, 2016-2017

Memberships
Member, American Society for Biochemistry and Molecular Biology
Member, Genetics Society of America

Joined OMRF’s scientific staff in 2022

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Recent Publications

Evatt JM, Sadli AD, Rapacz BK, Chuong HH, Meyer RE, Ridenour JB, Donczew R, Dawson DS. Centromere pairing enables correct segregation of meiotic chromosomes. Curr Biol, 2024 April, PMID: 38670094, PMCID: PMC11111343

Warfield L, Donczew R, Mahendrawada L, Hahn S. Yeast Mediator facilitates transcription initiation at most promoters via a Tail-independent mechanism. Mol Cell 82:4033-4048.e7, 2022 Nov, PMID: 36208626, PMCID: PMC9637718

Selected Publications

Warfield L, Donczew R, Mahendrawada L, Hahn S. (2022) Yeast Mediator facilitates transcription initiation at most promoters via a Tail-independent mechanism. Mol Cell. S1097-2765(22)00905-4. Epub ahead of print. PMID: 36208626.

Donczew R, Hahn S. (2021) BET family members Bdf1/2 modulate global transcription initiation and elongation in Saccharomyces cerevisiae. eLife 10:e69619. PMID: 34137374, PMCID: PMC8266393.

Donczew R*, Warfield L*, Pacheco D, Erijman A, Hahn S. (2020) Two roles for the yeast transcription coactivator SAGA and a set of genes redundantly regulated by TFIID and SAGA. eLife 9:e50109. PMID: 31913117, PMCID: PMC6977968.

Donczew R, Hahn S. (2018) Mechanistic differences in transcription initiation at TATA-less and TATA-containing promoters. Mol Cell Biol. 38(1):e00448-17. PMID: 29038161, PMCID: PMC5730718.

Cell Cycle & Cancer Biology Research Program, MS 48
825 NE 13th Street
Oklahoma City, Oklahoma 73104

E-mail: Rafal-Donczew@omrf.org

For media inquiries, please contact OMRF’s Office of Public Affairs at news@omrf.org.

Magdalena Donczew, Ph.D.
Assistant Staff Scientist

John Ridenour, Ph.D.
Assistant Staff Scientist

Cheri Rutledge
Administrative Assistant III

Denna Mills
Administrative Assistant II