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Biological Functions of Ub and SUMO

These two PTMs are highly regulated and can target a protein and assemble a monomodification or assemble more complex polymeric modifications consisting of branched and mixed chains comprising different lengths and linkages. For example, the process of ubiquitination can involve the targeting of a protein for monomodification with subsequent extension by the covalent addition of other ubiquitin proteins to the e-amino group of one of ubiquitin's

seven internal lysines (Lys 6, 11, 27, 29, 33, 48, and 63) or the a-amino group of its N-terminal methionine [15, 16]. The type of ubiquitin chain assembly on a modified protein directly impacts the protein-specific biological function within the cell. For example, modification of a protein by polyubiquitination chain assembly through the internal lysine 48-amino-acid residues of ubiquitin results in the protein being targeted for degradation in the 26S proteosome complex [17]. Similarly, these different types of chain assemblies impact the specific biological function of the SUMOylated proteins [18, 19].

These two PTMs can be involved in a multitude of important and diverse biological functions: (i) independently, such as in protein endocytosis in the case of ubiquitination [20, 21] and transcriptional activity in the case of SUMOylation [22, 23]; (ii) in combination with each other, known as cross talk, such as in DNA damage, replication, and repair [24-26]; and (iii) cross talk with other PTMs, for example, cross talk between ubiquitination and phosphorylation such as in regulation of E3 ligase activity [27] and cross talk between acetylation and SUMOylation in regulating p53-dependent gene transcription by the promotion and inhibition of p53 binding to DNA and chromatin [28]. Dysregulation of these ubiquitination and SUMOylation pathways has a substantial impact on the progression of a number of disease states including a number of cancers [29, 30] and neurodegenerative diseases [31, 32].

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