For Prospective Students and Postdocs

The Tretyakova group is currently looking to add several graduate students and postdocs to our team. 

Epigenetic Inhibitors

Many diseases are characterized by epigenetic deregulation, and epigenetic proteins such as histone deacetylases (HDAC) are important targets for anticancer therapies. Ten Eleven Translocation Dioxygenases (TET proteins) play an important role in epigenetic regulation by removing repressive 5-methyl-dC marks in DNA. These proteins sequentially oxidize 5-MethylC to hmC, fC, and carboxylC using catalytic iron and α-ketoglutarate cofactor.

We are employing structure-based design to engineering bisubstrate inhibitors that contain both 5-methylcytosine and α -KG mimics connected by a flexible linker. Several molecules have already been synthesized using Sonogashira cross-coupling and hydroxamate synthesis and are currently being tested for biological activity against recombinant protein and in human cells using a mass spectrometry base assay. More analogues will be prepared. We are also developing a FRET-based high throughput screening assay that will enable us to identify additional small molecule inhibitors of TET. Ultimately, potent and selective inhibitors of TET will be useful as  biological probes and potential leads for future epigenetic therapies of cancer and other diseases.

Unnatural Nucleosides as Potential SARS COVID-19 therapies

Remdesivir is an antiviral drug currently used for the treatment of COVID-19. Remdesivir is a nucleoside analog that is bioactivated to the corresponding triphosphate and is incorporated in viral RNA by COVID RNA polymerase, causing premature chain termination.  We are collaborating with Prof. Suse Broyde (NYU) and Courtney Aldrich (UMN) to develop novel analogs of remdesivir that exhibit improved activity and selectivity against SARS COVID-19. This project involves structure based drug design, organic synthesis, and development of novel enzymatic assays for screening drug candidates. 

DNA damage and aging

DNA damage is hypothesized to play a key role in aging because it can cause cell senescence. DNA repair defects lead to premature aging. We are collaborating with Laura Niedernhofer (Director, Institute on the Biology of Aging and Metabolism) to characterize the role of DNA adducts in aging and to develop sensitive and predictive biomarkers of aging. Both environmental and endogenous sources of DNA damage will be investigated using advanced mass spectrometry tools. 

Figure from Freitas et al   https://pubmed.ncbi.nlm.nih.gov/21600302/

Epigenetics of Alzheimer’s disease

Patients with Alzheimer’s disease (AD) exhibit significant changes in gene expression patterns, leading to cognitive impairment. We are investigating the role of N6-methyl-dA, a novel epigenetic mark recently discovered in humans, in epigenetic deregulation associated with AD. This project involves quantification of N6-methyl-dA in the human brain, mapping N6-methyl-dA across the human genome, and discovering protein “readers” of this novel mark using mass spectrometry based proteomics.

DNA-protein Cross-links in Gene Regulation

We recently discovered that naturally occurring 5-formyl-dC residues in DNA can form reversible Schiff base conjugates with Lys sidechains of histone proteins. This project will investigate the role of such cross-links in epigenetic regulation by quantifying 5-formyl-dC-Lys conjugates in cells via mass spectrometry, mapping conjugation sites via next generation sequencing, and constructing hydrolytically stable structural mimics of 5-formyl-dC-Lys conjugates that can be investigated for their effects on DNA replication and transcription.