Research - Peter 't Hart

Molecular Biochemistry

Deadenylation of mRNA by the CCR4-NOT complex

Almost all mRNAs produced by the human body are decorated with a stretch of adenosine residues on their 5’ end known as a poly(A) tail. The tail and is important for mRNA stability and translational activity. The length of the poly(A) tail is dynamically regulated throughout the mRNA's lifespan, with the removal of adenosine residues termed deadenylation.

Although there are multiple deadenylases in the human genome, the CCR4-NOT complex has been identified as the main regulator of this process. The complex is organized around the core scaffold protein CNOT1, with CNOT6 and CNOT7 functioning as the catalytic deadenylases. The remaining subunits of the complex serve as recruitment domains for other proteins with diverse functions or directly recruit RNA for deadenylation.

We use a chemical biology approach to elucidate the functional roles of the non-catalytic subunits of the CCR4-NOT complex. To achieve this, we develop inhibitory peptides designed to specifically disrupt their recruitment functions. Furthermore, by identifying which domains recruit specific mRNAs, we anticipate being able to predict their potential contributions to disease pathogenesis. Once this has been established, we will further investigate whether these inhibitory peptides can be developed into therapeutic agents.