View source for 8upf


==Cryo-EM structure of the human nucleosome core particle in complex with RNF168-UbcH5c==
<StructureSection load='8upf' size='340' side='right'caption='[[8upf]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8upf]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UPF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UPF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8upf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8upf OCA], [https://pdbe.org/8upf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8upf RCSB], [https://www.ebi.ac.uk/pdbsum/8upf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8upf ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RN168_HUMAN RN168_HUMAN] Defects in RNF168 are the cause of Riddle syndrome (RIDDLES) [MIM:[https://omim.org/entry/611943 611943]. Riddle syndrome is characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. Defects are probably due to impaired localization of TP53BP1 and BRCA1 at DNA lesions.<ref>PMID:19203578</ref> 
== Function ==
[https://www.uniprot.org/uniprot/RN168_HUMAN RN168_HUMAN] E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).<ref>PMID:19203578</ref> <ref>PMID:19203579</ref> <ref>PMID:20550933</ref> <ref>PMID:22713238</ref> <ref>PMID:22373579</ref> <ref>PMID:22705371</ref> <ref>PMID:22742833</ref> <ref>PMID:22980979</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
RNF168 plays a central role in the DNA damage response (DDR) by ubiquitylating histone H2A at K13 and K15. These modifications direct BRCA1-BARD1 and 53BP1 foci formation in chromatin, essential for cell-cycle-dependent DNA double-strand break (DSB) repair pathway selection. The mechanism by which RNF168 catalyzes the targeted accumulation of H2A ubiquitin conjugates to form repair foci around DSBs remains unclear. Here, using cryoelectron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy, and functional assays, we provide a molecular description of the reaction cycle and dynamics of RNF168 as it modifies the nucleosome and recognizes its ubiquitylation products. We demonstrate an interaction of a canonical ubiquitin-binding domain within full-length RNF168, which not only engages ubiquitin but also the nucleosome surface, clarifying how such site-specific ubiquitin recognition propels a signal amplification loop. Beyond offering mechanistic insights into a key DDR protein, our study aids in understanding site specificity in both generating and interpreting chromatin ubiquitylation.

Mechanisms of RNF168 nucleosome recognition and ubiquitylation.,Hu Q, Zhao D, Cui G, Bhandari J, Thompson JR, Botuyan MV, Mer G Mol Cell. 2024 Mar 7;84(5):839-853.e12. doi: 10.1016/j.molcel.2023.12.036. Epub , 2024 Jan 18. PMID:38242129<ref>PMID:38242129</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8upf" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
*[[3D structures of ubiquitin conjugating enzyme|3D structures of ubiquitin conjugating enzyme]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Botuyan MV]]
[[Category: Cui G]]
[[Category: Hu Q]]
[[Category: Mer G]]
[[Category: Zhao D]]