Discipline: Chemistry and Chemical Sciences
Subcategory: Chemistry (not Biochemistry)
Medinat Akindele - University of Minnesota
Introduction: DNA protein cross-links (DPCs) are bulky DNA lesions which are formed when a protein is covalently trapped on DNA in the presence of bis-electrophiles or reactive oxygen species. DPCs can stall DNA replication and transcription, leading to toxicity and mutations, if not repaired. DPCs are induced by chemotherapeutic agents used for the treatment of cancer such as cisplatin, platinum compounds, and nitrogen mustards. In addition, DPCs have been shown to accumulate in the brain and the heart as a result of exposure to endogenous aldehydes and reactive oxygen species. My aim is to synthesize site-specific model DPCs that can be used in future biological studies to determine the mechanisms of DPC repair and polymerase bypass. As part of this project, I am synthesizing a modified nucleoside phosphoramidite building block containing reactive aldehyde group. This phosphoramidite will be later incorporated into DNA via solid phase synthesis. This DNA residue will be later on used for covalently trapping of proteins to generate model site-specific DPCs. Methods: The synthesis of the phosphoramidite follows the procedures reported by Todor Angelov et. al. (Angelov, Todor, Angelo Guainazzi, and Orlando D. Schärer. “Generation of DNA interstrand cross-links by post-synthetic reductive amination.” Organic letters 11.3 (2009): 661-664.) Anticipated Results: DNA will be synthesized using the phosphoramidite. We will use mass spectrometry-based proteomics to identify protein candidates for DNA protein cross-linking. The biological activity of the cross-link will be studied in order to evaluate its potential in cancer research. Future Work: We will continue synthesizing the phosphoramidite building block. DNA will be cross-linked in vitro with peptides and proteins.
Not SubmittedFunder Acknowledgement(s): Undergraduate Research Opportunities Program
Faculty Advisor: Suresh Pujari, spujari@umn.edu
Role: I synthesized some of the molecules and purified most of them leading up to the phosphoramidite.