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| | <StructureSection load='4reb' size='340' side='right'caption='[[4reb]], [[Resolution|resolution]] 4.20Å' scene=''> | | <StructureSection load='4reb' size='340' side='right'caption='[[4reb]], [[Resolution|resolution]] 4.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4reb]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4REB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4REB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4reb]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4REB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4REB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SM:SAMARIUM+(III)+ION'>SM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 4.2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rea|4rea]], [[4rec|4rec]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SM:SAMARIUM+(III)+ION'>SM</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FAN1, KIAA1018, MTMR15 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4reb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4reb OCA], [https://pdbe.org/4reb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4reb RCSB], [https://www.ebi.ac.uk/pdbsum/4reb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4reb ProSAT]</span></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=4reb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4reb OCA], [http://pdbe.org/4reb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4reb RCSB], [http://www.ebi.ac.uk/pdbsum/4reb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4reb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/FAN1_HUMAN FAN1_HUMAN]] Karyomegalic interstitial nephritis. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/FAN1_HUMAN FAN1_HUMAN] Karyomegalic interstitial nephritis. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FAN1_HUMAN FAN1_HUMAN]] Nuclease required for maintenance of chromosomal stability. Plays a key role in DNA repair of DNA interstrand cross-links (ICL) by being recruited to sites of DNA damage by monoubiquitinated FANCD2. Specifically involved in repair of ICL-induced DNA breaks by being required for efficient homologous recombination, possibly in the resolution of homologous recombination intermediates. Not involved in DNA double-strand breaks resection. Has both endonuclease activity toward 5'-flaps and 5'-exonuclease activity: may act in concert with the 3'-flap-specific enzymes to unhook the ICL by cleaving the lagging-strand template.<ref>PMID:20603015</ref> <ref>PMID:20603016</ref> <ref>PMID:20603073</ref> <ref>PMID:20671156</ref> | + | [https://www.uniprot.org/uniprot/FAN1_HUMAN FAN1_HUMAN] Nuclease required for maintenance of chromosomal stability. Plays a key role in DNA repair of DNA interstrand cross-links (ICL) by being recruited to sites of DNA damage by monoubiquitinated FANCD2. Specifically involved in repair of ICL-induced DNA breaks by being required for efficient homologous recombination, possibly in the resolution of homologous recombination intermediates. Not involved in DNA double-strand breaks resection. Has both endonuclease activity toward 5'-flaps and 5'-exonuclease activity: may act in concert with the 3'-flap-specific enzymes to unhook the ICL by cleaving the lagging-strand template.<ref>PMID:20603015</ref> <ref>PMID:20603016</ref> <ref>PMID:20603073</ref> <ref>PMID:20671156</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Human FANCD2-associated nuclease 1 (FAN1) is a DNA structure-specific nuclease involved in the processing of DNA interstrand crosslinks (ICLs). FAN1 maintains genomic stability and prevents tissue decline in multiple organs, yet it confers ICL-induced anti-cancer drug resistance in several cancer subtypes. Here we report three crystal structures of human FAN1 in complex with a 5' flap DNA substrate, showing that two FAN1 molecules form a head-to-tail dimer to locate the lesion, orient the DNA and unwind a 5' flap for subsequent incision. Biochemical experiments further validate our model for FAN1 action, as structure-informed mutations that disrupt protein dimerization, substrate orientation or flap unwinding impair the structure-specific nuclease activity. Our work elucidates essential aspects of FAN1-DNA lesion recognition and a unique mechanism of incision. These structural insights shed light on the cellular mechanisms underlying organ degeneration protection and cancer drug resistance mediated by FAN1.
| + | |
| | | | |
| - | Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer.,Zhao Q, Xue X, Longerich S, Sung P, Xiong Y Nat Commun. 2014 Dec 11;5:5726. doi: 10.1038/ncomms6726. PMID:25500724<ref>PMID:25500724</ref>
| + | ==See Also== |
| - | | + | *[[Dual specificity phosphatase 3D structures|Dual specificity phosphatase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4reb" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Longerich, S]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Sung, P]] | + | [[Category: Longerich S]] |
| - | [[Category: Xiong, Y]] | + | [[Category: Sung P]] |
| - | [[Category: Xue, X]] | + | [[Category: Xiong Y]] |
| - | [[Category: Zhao, Q]] | + | [[Category: Xue X]] |
| - | [[Category: Fancid2]]
| + | [[Category: Zhao Q]] |
| - | [[Category: Hjc]]
| + | |
| - | [[Category: Hydrolase-dna complex]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Sap]]
| + | |
| - | [[Category: Structure specific nuclease]]
| + | |
| - | [[Category: Tpr]]
| + | |
| Structural highlights
Disease
FAN1_HUMAN Karyomegalic interstitial nephritis. The disease is caused by mutations affecting the gene represented in this entry.
Function
FAN1_HUMAN Nuclease required for maintenance of chromosomal stability. Plays a key role in DNA repair of DNA interstrand cross-links (ICL) by being recruited to sites of DNA damage by monoubiquitinated FANCD2. Specifically involved in repair of ICL-induced DNA breaks by being required for efficient homologous recombination, possibly in the resolution of homologous recombination intermediates. Not involved in DNA double-strand breaks resection. Has both endonuclease activity toward 5'-flaps and 5'-exonuclease activity: may act in concert with the 3'-flap-specific enzymes to unhook the ICL by cleaving the lagging-strand template.[1] [2] [3] [4]
See Also
References
- ↑ MacKay C, Declais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, Hofmann K, Gartner A, West SC, Helleday T, Lilley DM, Rouse J. Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell. 2010 Jul 9;142(1):65-76. doi: 10.1016/j.cell.2010.06.021. PMID:20603015 doi:http://dx.doi.org/10.1016/j.cell.2010.06.021
- ↑ Kratz K, Schopf B, Kaden S, Sendoel A, Eberhard R, Lademann C, Cannavo E, Sartori AA, Hengartner MO, Jiricny J. Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell. 2010 Jul 9;142(1):77-88. doi: 10.1016/j.cell.2010.06.022. PMID:20603016 doi:http://dx.doi.org/10.1016/j.cell.2010.06.022
- ↑ Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiacovo MP, Elledge SJ. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010 Jul 9;39(1):36-47. doi: 10.1016/j.molcel.2010.06.023. PMID:20603073 doi:http://dx.doi.org/10.1016/j.molcel.2010.06.023
- ↑ Liu T, Ghosal G, Yuan J, Chen J, Huang J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science. 2010 Aug 6;329(5992):693-6. doi: 10.1126/science.1192656. Epub 2010 Jul , 29. PMID:20671156 doi:http://dx.doi.org/10.1126/science.1192656
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