Abstract
There is growing evidence highlighting the importance of monoubiquitination as part of the histone code. Monoubiquitination, the covalent attachment of a single ubiquitin molecule at specific lysines of histone tails, has been associated with transcriptional elongation and the DNA damage response. Sites function as scaffolds or docking platforms for proteins involved in transcription or DNA repair; however, not all sites are equal, with some sites resulting in actively transcribed chromatin and others associated with gene silencing. All events are written by E3 ubiquitin ligases, predominantly of the RING (really interesting new gene) finger type. One of the most well-studied events is monoubiquitination of histone H2B at lysine 120 (H2Bub1), written predominantly by the RING finger complex RNF20-RNF40 and generally associated with active transcription. Monoubiquitination of histone H2A at lysine 119 (H2AK119ub1) is also well-studied, its E3 ubiquitin ligase constituting part of the Polycomb Repressor Complex 1 (PRC1), RING1B-BMI1, associated with transcriptional silencing. Both modifications are activated as part of the DNA damage response. Histone monoubiquitination is a key epigenomic event shaping the chromatin landscape of malignancy and influencing how cells respond to DNA damage. This review discusses a number of these sites and the E3 RING finger ubiquitin ligases that write them.
Highlights
Histones are basic proteins, with histone H2A, H2B, H3 and H4 constituting the core structure of the nucleosome as an octamer complex around which 147 bp of DNA wrap
Loss of Ring Finger Protein 20 (RNF20) has been linked with an inflammatory phenotype in colorectal cancer [71], while loss of RNF40 would appear to have a protective effect against the development of an inflammatory phenotype in the same cancer [85], both involving NF-κB signalling
The rat orthologue of RNF40, has been shown to polyubiquitinate Syntaxin 1, which is part of the neurotransmitter release machinery with links to learning and memory behaviour, facilitating its degradation via the ubiquitin proteasome [87]. It is currently unclear whether RNF20 and RNF40 may partner with different E2 enzymes for the purpose of ubiquitinating these non-histone substrates
Summary
With histone H2A, H2B, H3 and H4 constituting the core structure of the nucleosome as an octamer complex around which 147 bp of DNA wrap. N-terminal tails of histones in the nucleosome protrude from this structure and undergo a range of covalent modifications including acetylation, methylation, SUMOylation, phosphorylation, protein isomerisation and ubiquitination [3,4,5]. While little is known about the effect of some of these ubiquitination events, others have been shown to have opposing effects in the context of their association with either active or silent chromatin, impacting on gene transcription [31,43,44] This fascinating dichotomy possibly relates to positioning within the nucleosome structure. K127 and K129 on histone tail H2A are ubiquitinated by E3 ligase activity of the Breast Cancer 1 (BRCA1)- BRCA1-Associated RING Domain Protein 1 (BARD1).
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