It is puzzling that the human genome has only slightly more genes than the fruit fly and only half the number of cauliflower. Obviously, the sheer number of genes alone cannot determine the complexity of human development and the sophisticated signalling systems that maintain homeostasis. In fact, the complexity of information from genome to proteome is greatly increased. Drivers for the complexity of the proteome are posttranslational modifications (PTMs), i.e. covalent modifications of polypeptides after translation.
The aim of this project is to shine light on a scientific mystery known for decades. We will elucidate the cellular roles and functions of diadenosine polyphosphates (ApnAs), which are formed in response to stress and are therefore called "alarmones", and their interactions with the PTM processes "AMPylation", i.e. the covalent modification of the target protein by adenosine monophosphate.
Our initial findings have unveiled the interaction between ApnAs and AMPylation for the first time. We are now embarking on a quest to discover, identify, and delineate new key players in AMPylation, elucidating their interplay with ApnAs. To achieve this, we will craft and employ novel chemical tools in proteome-wide studies within living cells.
We will further explore the molecular role of a previously identified protein using ApnA-based probes. This protein, now known as Rlig1 (previously C12orf29), has been identified as a "5'-3' RNA ligase"—the first of its kind discovered in human cells. Emerging evidence suggests that Rlig1 plays a critical role in RNA repair mechanisms within human cells, a process that remains inadequately examined and understood. Consequently, our research will focus on comprehensively understanding the molecular dynamics, functionalities, and the specific contributions of Rlig1 to RNA repair processes.
Overall, this project will bring significant new advances in this under-researched field and provide a guide for future translational research in the fight against disease
