Exploring N-terminal acetyltransferases with functional genomics

Protein N-terminal acetylation is a common protein modification in eukaryotes, but we still know very little about how this small chemical tag affects our cells. We know that the acetyl group can affect protein behavior by activating proteins, telling them where to go inside the cell, or decide whether a protein should be degraded. A group of enzymes called N-terminal acetyltransferases (NATs) performs N-terminal acetylation. Deficient N-terminal acetylation can lead to physical or intellectual disabilities as well as genetic syndromes that cause premature death, and is suspected to have a role in cancer development. Despite the fact that its importance for human development and health has been known for many years, the biological function(s) of N-terminal acetylation remain enigmatic. The main aim of the NatFUGE project was to systematically investigate the genes encoding N-terminal acetyltransferases (NATs) to reveal molecular mechanisms that underlay the cellular importance of N-terminal acetylation. To this end, I initiated a collaboration with world-leading experts in functional genomics at the Donnelly Center for Cellular and Biomolecular Research in Toronto, Canada. To identify genes that are essential for cell survival in the absence of NAT genes, I used CRISPR/Cas9 genetic scissors to systematically inactivate individual genes in normal cells as well as in cells not expressing a particular NAT enzyme. Genetic interactions occur when mutations in two or more genes combine to make an unexpected phenotype. Genes that are involved the same biological process have a tendency to share genetic interactions. By identifying genetic interactions of non-essential NAT genes, we are now a step closer to a global genetic interaction network for N-terminal acetyltransferases. This will allow us to better understand the functional importance of N-terminal acetylation and how this important protein modification affects various biological processes. Through this work, I have identified several genes likely regulated by N-terminal acetylation. Future work will focus on validating and characterizing NAT-related phenotypes that correspond to the signaling pathways that were brought forth from these genetic studies. In sum, the NatFUGE project will shed new light on which cellular processes that are regulated by N-terminal acetylation.

De siste årene har det vært økt fokus på sammenhengen mellom N-terminal acetylering og sykdom. NatFUGE var et grunnforskningsprosjekt som tok sikte på å skaffe til veie ny kunnskap om denne livsviktige protein modifiseringen, ved å bruke nyskapende funksjonell genomforskning som metode. Ved å identifisere genetiske interaksjoner av ikke-essensielle NAT-gener, er vi nå et skritt nærmere kartleggingen av et globalt genetisk interaksjonsnettverk for N-terminal acetyltransferaser. Denne banebrytende studien vil danne grunnlaget for fremtidige forskning på en svært viktig, men ofte oversett, molekylær bidragsyter til menneskelig utvikling og helse. NatFUGE studien vil sannsynligvis være relevant innenfor biomedisinsk forskning, inkludert forståelsen av hvordan cellene regulerer et sunt og balansert proteom, og kan derfor ha klinisk betydning.

N-terminal acetylation is a ubiquitous protein modification among eukaryotes, whose function remains enigmatic. The project "Exploring N-terminal acetyltransferases with functional genomics" will for the first time systematically investigate genetic interactions of genes encoding N-terminal acetyltransferases in yeast as well as human CRISPR based knockout models. The project brings together international multidisciplinary expertise on N-terminal acetylation and functional genomics, and has a huge potential to expand the biological understanding of this highly abundant and important protein modification.