Eugene Valkov, D.Phil.
- Center for Cancer Research
- National Cancer Institute
- Building 560, Room 11-83C
- Frederick, MD 21702
Eugene Valkov's research group investigates molecular mechanisms that regulate messenger RNA stability. Our team developed procedures for the recombinant production and biochemical characterization of many human factors that have critical roles in the late stages of gene expression. Our approach is to study reconstituted systems through biochemistry and biophysical analysis to derive working models of their interactions and mechanisms of action. Collaborating with colleagues at the Center for Structural Biology, we utilize cryogenic electron microscopy with single-particle analysis to obtain a high-resolution structural view of the systems under study to understand the molecular mechanism. Our work has broad implications beyond pure research. Recently, we have begun to apply our knowledge and access to a unique panel of biological reagents to improve and inform the development of the next generation of RNA-based therapeutics to target cancer and other diseases.
Areas of Expertise
The scientific goal of the laboratory is to study the events that determine the molecular ‘fate’ of mRNA in the cytoplasm. We focus on the mechanisms that regulate the removal of structures that protect mRNA from degradation: the poly(A) tail at the 3′-end, in a process known as deadenylation, and the 7-methylguanylate cap at the 5′-end, or decapping. We wish to understand what determines the specificity of these processes and their integration with other stages of the gene expression pathway.
Our principal approach to studying these molecular events is to reconstitute the relevant regulatory macromolecular complexes from highly purified recombinant components and to study them in vitro. To this end, we employ biochemical assays and biophysical approaches to study the interactions between the components using the instrumentation and facilities available at the Biophysical Resource, part of the Center for Structural Biology. To gain a deeper appreciation of the molecular mechanism, we extensively collaborate with our colleagues at the Center for Structural Biology to determine high-resolution cryoEM structures by single-particle analysis using the data collected on the Titan Krios and Talos Arctica microscopes. Among our recent achievements is the reconstitution of the complete human CCR4-NOT deadenylation complex and the entire network of principal human decapping factors. These unique biochemical tools and reagents enable us to study the 5′-to-3′ mRNA decay pathway with unprecedented precision and control.
To relate biochemical and structural insights to function, we test our derived hypotheses directly in human cells; for example, by complementing different variants in cell lines where the expression of individual molecular factors has been knocked out by CRISPR gene editing. This approach has proved very powerful in validating and mapping interactions in vivo. We use high-throughput short-read sequencing with bioinformatic analysis to survey cellular transcriptome and translatome dynamics. We also employ long-read direct RNA sequencing approaches to study mRNA metabolism using Oxford Nanopore instruments available at the RNA Biology Laboratory. A long-standing goal of the laboratory is to achieve sufficient understanding to rebuild entire functionally-relevant regulatory processes of mRNA decay in a test tube. Such a platform offers a unique toolkit to optimize mRNA-based therapeutics for stability and expression and to introduce new design features to target cancer more effectively.
Relevance to Cancer
Dysregulation of posttranscriptional control contributes to autoimmune disease, neurodegeneration, and especially toward oncogenic transformation. Our research is focused on the fundamental biological discovery, which is vital for progress in addressing urgent challenges of age-related diseases. Improved mechanistic understanding of the turnover and translation of mRNA holds enormous potential to provide immediate new vantage points for therapeutic intervention in tumor progression and metastasis.
Reconstitution of recombinant human CCR4-NOT reveals molecular insights into regulated deadenylation
Eugene Valkov, D.Phil.
Eugene Valkov received his bachelor’s degree in molecular biology from the University of Portsmouth in the U.K. and his doctoral degree in molecular biophysics from the Department of Biochemistry at the University of Oxford. His principal postdoctoral work in RNA biology was with Murray Stewart at the MRC Laboratory of Molecular Biology in the U.K., where he investigated the molecular mechanisms of mRNA export and became interested in posttranscriptional regulation. In 2014, Eugene joined the department headed by Elisa Izaurralde at the Max Planck Institute for Developmental Biology in Tübingen, Germany. Three years later, in 2017, Eugene was promoted to the group leader at the Max Planck Institute. He joined the NCI in 2019 as a tenure-track Stadtman Investigator at the newly formed RNA Biology Laboratory. In addition to his research activities, Eugene serves on the editorial board of the Journal of Structural Biology: X. He is also the guest editor of the Current Opinion in Structural Biology section on Protein Nucleic Acid Interactions 2022 and co-editor of the Methods in Molecular Biology collection of experimental protocols focused on deadenylation.
About the Lab
- We are a basic research laboratory and part of the largest biomedical research institution in the world, the NIH Intramural Program, with 1,200 principal investigators and over 4,000 postdoctoral fellows conducting basic, translational, and clinical research.
- We are among the 250 basic and clinical research labs comprising the Center for Cancer Research, the largest research division of the National Cancer Institute.
- Led by an experienced Principal Investigator focused on promoting research excellence and mentoring a diverse, friendly, and supportive research team.
What We Offer
- Unique research environment supported by stable, generous core funding to enable us to address long-term, outstanding questions in RNA biology.
- Collaboration opportunities with leading academic groups and industry.
- Unrestricted access to world-class core research facilities and instrumentation, such as the Titan Krios G4 equipped with a Falcon4 detector and a Selectris energy filter.
- Interaction opportunities with exceptional basic scientists and clinicians at the NIH.
- Numerous opportunities for exposure at the NIH and international conferences.
- Strong focus on individual mentoring, developing research expertise, acquiring transferable skills, and career development.
- Professional assistance and support with J1 or H1 visa applications for international scientists at the Division of International Services.
- Generous financial support with relocation costs.
- Salary information for postdoctoral candidates.
- Salary information for postbaccalaureate candidates.
- Further information about training at the NIH and associated benefits.
Looking to Join Us?
At the postbaccalaureate level:
- GPA equal to 3.7 or above in biochemistry, molecular biology, chemistry, or a related major from a reputable higher education institution.
- Enthusiasm for research and science.
- Demonstrated ability to work in a team.
- Strong organizational skills.
- Some biochemistry experience in a research lab is preferred but not essential.
At the postdoctoral level:
- We always welcome inquiries from motivated, enthusiastic, team-oriented biochemists, molecular biologists, and structural biologists interested in RNA-related mechanisms.
- A prerequisite is a Ph.D. or postdoctoral experience in biochemistry, structural biology, or molecular biology from a reputable higher education institution or a research institute.
- Another prerequisite is first-author, or a joined first-author publication or a preprint. Publications in revision without a preprint will be considered on a case-by-case basis.
- Experience with cryoEM workflow will be considered a strong plus.
We also welcome inquiries from prospective graduate students seeking a Ph.D. rotation in a host lab as part of the NIH Graduate Partnerships Program.
If you are an undergraduate or a high school student, we may offer an opportunity to experience research as part of the Summer Internship Program in Biomedical Research.
How to Apply?
- Send an email to firstname.lastname@example.org
- Include your CV, contact details for 2-3 referees, and a one-page statement describing your research experience and why you want to join the lab.