Abstract
Deciphering ubiquitin proteoform signaling and its role in disease has been a long-standing challenge in the field. The effects of ubiquitin modifications, its relation to ubiquitin-related machineries, and its signaling output has been particularly limited by its reconstitution and means of characterization. Advances in genetic code expansion have contributed towards addressing these challenges by precision incorporation of unnatural amino acids through site selective codon suppression. This review discusses recent advances in studying the 'writers', 'readers', and 'erasers' of the ubiquitin code using genetic code expansion. Highlighting strategies towards genetically encoded protein ubiquitination, ubiquitin phosphorylation, acylation, and finally surveying ubiquitin interactions, we strive to bring attention to this unique approach towards addressing a widespread proteoform problem.