The Ubiquitin System: More Than Just Protein Degradation

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Transcription factors are key regulators of gene transcription in eukaryotes. These proteins bind to specific DNA sequences in the 5’ region of a gene known as the promoter or enhancer region. The structure of a transcription factor consists of a DNA binding domain that interacts with the genome, and other domains that interact with other transcription factors, coactivators, RNA polymerases, silencers, and enhancers. Enhancers may initially bind to a region of the genome far from the gene they enhance, and bind to the transcription factor complex through chromatin looping1. Some components of a transcription factor complex are specific to the gene being primed for transcription and other components may be tissue-specific2. Or, transcription factors may be able to recognize several genes, but the target genes are expressed in a tissue-specific manner3.


Transcription factors can be grouped into families and there are four common DNA binding domain structures that exist in eukaryotes. These motifs are basic helix-loop-helix (consisting of a DNA-binding helix), helix-turn-helix (comprising a bundle of three helices), zinc finger (for which the DNA-binding helices require the presence of a zinc ion), and leucine zipper (in which a chain of leucine amino acids holds together two halves of a DNA-binding dimer)4,5. Basic helix-loop-helix transcription factors can be further subdivided into six subclasses based on the DNA and/or protein sequences they are able to bind. Common basic helix-loop-helix transcription factors include Myc, HIF, and MyoD6. The helix-turn-helix motif has evolved over time and is found in both prokaryotes and eukaryotes and in proteins besides transcription factors as well. Some common helix-turn-helix transcription factors include Cyclin, Myb, and BRCA25. Zinc finger domains are similarly present in transcription factors and other proteins that help to regulate cell cycle progression including apoptosis and protein folding7. Zinc finger transcription factors are also easily engineered to recognize any 18-base pair-long sequence of DNA to experimentally drive transcription of a specific gene8. Leucine zipper transcription factors are found exclusively in eukaryotes – both animals and plants9. A common class of leucine zipper transcription factors are the C/EBP proteins, which were the first to be identified with this motif10.


The requirement for transcription factor complexes, and not a single transcription factor binding to a gene, to initiate transcription is one way this process is regulated. Additionally, transcriptional repressors, or proteins that bind to transcription factor complexes and inhibit gene transcription, is another method of regulation. Transcriptional repressors may bind to a specific DNA sequence, or may bind as part of a complex11. Unlike activators of transcription that may bind at the gene site or elsewhere in the genome, repressors are most frequently observed to bind in the 5’ region of the gene being repressed4. Repressors also play other roles in the regulation of transcription. They have been implicated in priming genes for future transcription, retaining RNA polymerase at a gene site, and as co-regulators in association with transcriptional activators12.

Detection of human CD31 (red) in FFPE breast adenocarcinoma by IF

The Process Of Ubiquitination.
The ubiquitination process begins with an E1 enzyme binding a molecule of Ubiquitin (Ub). The Ub is then transferred to an E2 enzyme, and then to an E3 ligase enzyme, which transfers the Ub moiety onto the appropriate substrate. The nature of the E2 enzyme determines the type of Ub linkage that will be created, and the E3 ligase selects the substrate (target protein) to be ubiquitinated. Target proteins can have one or more Ub moieties, and linear or branched Ub chains. The length and conformation of the Ub chain(s) determine the fate and function of the modified target protein.


Below is the entire list of targets involved in Ubiquitination research. Can’t find what you are looking for? Bethyl offers a custom antibody service.




1. Buetow L, Huang DT. 2016. Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Biol. 17(10):626-42. PMID: 27485899.

2. Ebner P, Versteeg GA, Ikeda F. 2017. Ubiquitin enzymes in the regulation of immune responses. Crit Rev Biochem Mol Biol. 52(4):425-460. PMID: 28524749.

3. Huang X, Dixit VM. 2016. Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res. 26(4):484-98. PMID: 27002218.

4. Landré V, Rotblat B, Melino S, Bernassola F, Melino G. 2014. Screening for E3-ubiquitin ligase inhibitors: challenges and opportunities. Oncotarget. 5(18):7988-8013.   PMID: 25237759.

5. Geiss-Friedlander R, Melchior F. 2007. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 8(12):947-56. PMID: 18000527.

6. Ronau JA, Beckmann JF, Hochstrasser M. 2016. Substrate specificity of the ubiquitin and Ubl proteases. Cell Res. 26(4):441-56. PMID: 27012468.

7. Senft D, Qi J, Ronai ZA. 2018. Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18(2):69-88. PMID: 29242641.

8. Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS. 2016. E2 enzymes: more than just middle men. Cell Res. 26(4):423-40. PMID: 27002219.