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| | ==Mono-ubiquitinated Fanconi Anemia ID complex bound to ICL DNA== | | ==Mono-ubiquitinated Fanconi Anemia ID complex bound to ICL DNA== |
| - | <StructureSection load='6vae' size='340' side='right'caption='[[6vae]], [[Resolution|resolution]] 3.50Å' scene=''> | + | <StructureSection load='6vae' size='340' side='right'caption='[[6vae]], [[Resolution|resolution]] 3.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6vae]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VAE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6VAE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6vae]] is a 6 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=6VAE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VAE FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6vae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vae OCA], [http://pdbe.org/6vae PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vae RCSB], [http://www.ebi.ac.uk/pdbsum/6vae PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vae ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.6Å</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=6vae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vae OCA], [https://pdbe.org/6vae PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vae RCSB], [https://www.ebi.ac.uk/pdbsum/6vae PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vae ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/FACD2_HUMAN FACD2_HUMAN]] Fanconi anemia. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/FANCI_HUMAN FANCI_HUMAN] Fanconi anemia. The disease is caused by variants affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UBC_HUMAN UBC_HUMAN]] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref> [[http://www.uniprot.org/uniprot/FACD2_HUMAN FACD2_HUMAN]] Required for maintenance of chromosomal stability. Promotes accurate and efficient pairing of homologs during meiosis. Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing. May participate in S phase and G2 phase checkpoint activation upon DNA damage. Plays a role in preventing breakage and loss of missegregating chromatin at the end of cell division, particularly after replication stress. Required for the targeting, or stabilization, of BLM to non-centromeric abnormal structures induced by replicative stress. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching.<ref>PMID:11239453</ref> <ref>PMID:11239454</ref> <ref>PMID:12086603</ref> <ref>PMID:12239151</ref> <ref>PMID:14517836</ref> <ref>PMID:15115758</ref> <ref>PMID:15314022</ref> <ref>PMID:15377654</ref> <ref>PMID:15454491</ref> <ref>PMID:15650050</ref> <ref>PMID:15661754</ref> <ref>PMID:15671039</ref> <ref>PMID:19465921</ref> | + | [https://www.uniprot.org/uniprot/FANCI_HUMAN FANCI_HUMAN] Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites. Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage.<ref>PMID:17412408</ref> <ref>PMID:17452773</ref> <ref>PMID:17460694</ref> <ref>PMID:19111657</ref> <ref>PMID:25862789</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions(1). These proteins are mutated in Fanconi anaemia, a disease in which patients are predisposed to cancer. The Fanconi anaemia pathway of ICL repair is activated when a replication fork stalls at an ICL(2); this triggers monoubiquitination of the ID complex, in which one ubiquitin molecule is conjugated to each of FANCI and FANCD2. Monoubiquitination of ID is essential for ICL repair by excision, translesion synthesis and homologous recombination; however, its function remains unknown(1,3). Here we report a cryo-electron microscopy structure of the monoubiquitinated human ID complex bound to DNA, and reveal that it forms a closed ring that encircles the DNA. By comparison with the structure of the non-ubiquitinated ID complex bound to ICL DNA-which we also report here-we show that monoubiquitination triggers a complete rearrangement of the open, trough-like ID structure through the ubiquitin of one protomer binding to the other protomer in a reciprocal fashion. These structures-together with biochemical data-indicate that the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions. Our findings also reveal how monoubiquitination in general can induce an alternative protein structure with a new function. |
| | + | |
| | + | DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex.,Wang R, Wang S, Dhar A, Peralta C, Pavletich NP Nature. 2020 Apr;580(7802):278-282. doi: 10.1038/s41586-020-2110-6. Epub 2020 Mar, 11. PMID:32269332<ref>PMID:32269332</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6vae" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pavletich, N P]] | + | [[Category: Pavletich NP]] |
| - | [[Category: Dna binding protein]]
| + | |
| - | [[Category: Dna binding protein-dna complex]]
| + | |
| - | [[Category: Dna clamp]]
| + | |
| Structural highlights
Disease
FANCI_HUMAN Fanconi anemia. The disease is caused by variants affecting the gene represented in this entry.
Function
FANCI_HUMAN Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites. Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions(1). These proteins are mutated in Fanconi anaemia, a disease in which patients are predisposed to cancer. The Fanconi anaemia pathway of ICL repair is activated when a replication fork stalls at an ICL(2); this triggers monoubiquitination of the ID complex, in which one ubiquitin molecule is conjugated to each of FANCI and FANCD2. Monoubiquitination of ID is essential for ICL repair by excision, translesion synthesis and homologous recombination; however, its function remains unknown(1,3). Here we report a cryo-electron microscopy structure of the monoubiquitinated human ID complex bound to DNA, and reveal that it forms a closed ring that encircles the DNA. By comparison with the structure of the non-ubiquitinated ID complex bound to ICL DNA-which we also report here-we show that monoubiquitination triggers a complete rearrangement of the open, trough-like ID structure through the ubiquitin of one protomer binding to the other protomer in a reciprocal fashion. These structures-together with biochemical data-indicate that the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions. Our findings also reveal how monoubiquitination in general can induce an alternative protein structure with a new function.
DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex.,Wang R, Wang S, Dhar A, Peralta C, Pavletich NP Nature. 2020 Apr;580(7802):278-282. doi: 10.1038/s41586-020-2110-6. Epub 2020 Mar, 11. PMID:32269332[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007 Apr 20;129(2):289-301. doi: 10.1016/j.cell.2007.03.009. Epub 2007 Apr , 5. PMID:17412408 doi:http://dx.doi.org/10.1016/j.cell.2007.03.009
- ↑ Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D, Mohan S, Schindler D, Arwert F, Pals G, Mathew CG, Waisfisz Q, de Winter JP, Joenje H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29(3):211-8. PMID:17452773
- ↑ Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007 Jun;14(6):564-7. Epub 2007 Apr 25. PMID:17460694 doi:http://dx.doi.org/nsmb1252
- ↑ Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:http://dx.doi.org/10.1016/j.molcel.2008.12.003
- ↑ Oka Y, Bekker-Jensen S, Mailand N. Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway. EMBO J. 2015 May 12;34(10):1385-98. PMID:25862789 doi:10.15252/embj.201490376
- ↑ Wang R, Wang S, Dhar A, Peralta C, Pavletich NP. DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex. Nature. 2020 Apr;580(7802):278-282. doi: 10.1038/s41586-020-2110-6. Epub 2020 Mar, 11. PMID:32269332 doi:http://dx.doi.org/10.1038/s41586-020-2110-6
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