| Structural highlights
Function
[BRE1A_HUMAN] Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1). H2BK120ub1 gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation (H3K4me and H3K79me, respectively). It thereby plays a central role inb histone code and gene regulation. The RNF20/40 complex forms a H2B ubiquitin ligase complex in cooperation with the E2 enzyme UBE2A or UBE2B; reports about the cooperation with UBE2E1/UBCH are contradictory. Required for transcriptional activation of Hox genes. Recruited to the MDM2 promoter, probably by being recruited by p53/TP53, and thereby acts as a transcriptional coactivator. Mediates the polyubiquitination of isoform 2 of PA2G4 in cancer cells leading to its proteasome-mediated degradation.[1] [2] [3] [4]
Publication Abstract from PubMed
Monoubiquitylation of histone H2B is a post-translational mark that plays key roles in regulation of transcription and genome stability. In humans, attachment of ubiquitin to lysine 120 of histone H2B depends on the activity of the E2 ubiquitin-conjugating enzyme, Ube2B, and the really interesting new gene (RING) E3 ligases, RING finger protein (RNF) 20 and RNF40. To better understand the molecular basis of this modification, we have solved the crystal structure of the RNF20 RING domain and show that it is a homodimer that specifically interacts with the Ube2B~Ub conjugate. By mutating residues at the E3-E2 and E3-ubiquitin interfaces, we identify key contacts required for interaction of the RNF20 RING domain with the Ube2B~Ub conjugate. These mutants were used to generate a structure-based model of the RNF20-Ube2B~Ub complex that reveals differences from other RING-E2~Ub complexes, and suggests how the RNF20-Ube2B~Ub complex might interact with its nucleosomal substrate. Additionally, we show that the RING domains of RNF20 and RNF40 can form a stable heterodimer that is active. Together, our studies provide new insights into the mechanisms that regulate RNF20-mediated ubiquitin transfer from Ube2B.
Structure and Function of the RING Domains of RNF20 and RNF40, Dimeric E3 Ligases that Monoubiquitylate Histone H2B.,Foglizzo M, Middleton AJ, Day CL J Mol Biol. 2016 Aug 25. pii: S0022-2836(16)30339-4. doi:, 10.1016/j.jmb.2016.07.025. PMID:27569044[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D. Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol Cell. 2005 Nov 23;20(4):601-11. PMID:16307923 doi:http://dx.doi.org/S1097-2765(05)01646-1
- ↑ Kim J, Hake SB, Roeder RG. The human homolog of yeast BRE1 functions as a transcriptional coactivator through direct activator interactions. Mol Cell. 2005 Dec 9;20(5):759-70. PMID:16337599 doi:http://dx.doi.org/10.1016/j.molcel.2005.11.012
- ↑ Liu Z, Oh SM, Okada M, Liu X, Cheng D, Peng J, Brat DJ, Sun SY, Zhou W, Gu W, Ye K. Human BRE1 is an E3 ubiquitin ligase for Ebp1 tumor suppressor. Mol Biol Cell. 2009 Feb;20(3):757-68. doi: 10.1091/mbc.E08-09-0983. Epub 2008 Nov, 26. PMID:19037095 doi:http://dx.doi.org/10.1091/mbc.E08-09-0983
- ↑ Kim J, Guermah M, McGinty RK, Lee JS, Tang Z, Milne TA, Shilatifard A, Muir TW, Roeder RG. RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells. Cell. 2009 May 1;137(3):459-71. doi: 10.1016/j.cell.2009.02.027. PMID:19410543 doi:10.1016/j.cell.2009.02.027
- ↑ Foglizzo M, Middleton AJ, Day CL. Structure and Function of the RING Domains of RNF20 and RNF40, Dimeric E3 Ligases that Monoubiquitylate Histone H2B. J Mol Biol. 2016 Aug 25. pii: S0022-2836(16)30339-4. doi:, 10.1016/j.jmb.2016.07.025. PMID:27569044 doi:http://dx.doi.org/10.1016/j.jmb.2016.07.025
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