Inhibition and induction of mRNA deadenylation

• Applicant: Professor Dr. Peter 't Hart
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570830502

Almost all mRNAs in the human body carry a stretch of adenosine residues at their ends known as the poly(A) tail. The tail is important for translational activity and stability of the mRNA and can be removed by deadenylases when an mRNA is not required anymore. A key player in mRNA deadenylation is the CCR4-NOT complex, which contains two catalytically active deadenylation subunits and various other components that are important for bringing mRNAs to the complex. The project has two parts, the first is to further understand the regulation of the CCR4-NOT complex. While the second will focus on using the function of the complex for the removal of unwanted mRNAs. In the first part, we will use generative artificial intelligence to develop peptides that block the CCR4-NOT subunit CNOT9. By blocking this part, we can investigate its role in mRNA deadenylation in more detail. The peptides will be optimized not only for efficient targeting of CNOT9, but also for their ability to enter cells. With a potent compound that can do so we can analyze which mRNAs get degraded via CNOT9 and which do not in cancer cells. Furthermore, we will be able to see which proteins CNOT9 interacts with to gain a deeper understanding of its mode of action. In the second project we will combine a peptide that binds CNOT9, with a so called peptide nucleic acid sequence which recognizes a specific mRNA. By combining these elements, we will force the target mRNA to get close to the CCR4-NOT complex and thereby get degraded. Using this strategy, we will be able to destroy disease causing mRNAs in cancer cells. An added advantage of using a stapled peptide is that this part also promotes cell permeability, and the reagents have the potential to be dosable without requiring special formulations that nucleotide based drugs normally need.

• DFG Programme: Research Grants