Species-specific aspects in eukaryotic mRNA translation modulation and their implications in diseases

Introduction

mRNA translation is a universally conserved process consisting of translating the genetic code into proteins, the primary building blocks of all living organisms. Translation is mainly operated by the ribosome, a hybrid molecule made of RNAs and proteins.

Translation in Eukaryotes

In most eukaryotes, at least two types of mRNA translation coexist in nearly all cells. Indeed, although the quasi-totality of the proteins is translated in the cytosol by the cytosolic ribosome, a small yet essential fraction of mRNA translation can take place in the mitochondria, the cell’s power plant.

Species-Specific Differences

While the mitochondrial translation process has proven to be substantially species-specific, numerous species-specific structural and regulatory differences also exist in the cytosolic translation process. These differences are present despite their relative conservation among eukaryotic species and are yet to be elucidated.

Research Objectives

We will use various structural and molecular biology methods to investigate, from a disease-related perspective, several species-specific aspects of mRNA translation modulation in mammals and in pathogenic parasites from the family of kinetoplastids. Our specific objectives are:

1. To investigate the molecular roles of several kinetoplastid-specific proteins involved in translation and evaluate their validity as pharmacophores.
2. To study mitochondrial translation in kinetoplastids and focus on its variable regulation in different forms of the parasites during their life-cycle (blood vs. insect stages).
3. To study cytosolic mRNA scanning for the start codon during translation initiation to:
   • Understand its molecular basis in different types of mRNAs (native and modified mRNAs, natural or artificial).
   • Investigate its alteration in colorectal cancer caused by the absence of a ribosomal RNA modification.

Expected Outcomes

Results will advance our knowledge of species-specific mRNA translation and open new perspectives for developing treatments against various human diseases and infections, including anti-parasite therapies, cancer therapy, and mRNA vaccines.