**1. Introduction**

Ubiquitination is a reversible post-translational modification process during which the highly conserved 76-aminoacid protein ubiquitin is conjugated to target proteins. Ubiquitin can be conjugated to a protein substrate via distinct mechanisms. Monoubiquitination is the attachment of a single ubiquitin molecule to a single lysine residue on a substrate protein, whereas multi-monoubiquitination is the conjugation of a single ubiquitin molecule to multiple lysine residues. Polyubiquitination occurs when ubiquitin molecules are attached end-to-end to a lysine residue on a substrate protein to form a poly-ubiquitin chain. In this case, ubiquitin molecules are conjugated through one of the seven lysine residues present on the ubiquitin itself (K6, K11, K27, K29, K33, K48, and 63) or the N-terminal methionine (M1). While most of the studies have described the role of specific polyubiquitination, such as K48-linked polyubiquitination for proteasomal degradation [1,2] or K63-linked polyubiquitination for vesicular tra fficking [3], emerging evidences implicate monoubiquitination and multi-monoubiquitination in controlling numerous aspects of protein function, such as degradation, subcellular localization, and protein–protein interaction. In this review, we focus on the role of monoubiquitin conjugation in normal physiology and genetic disease.
