4ric

From Proteopedia

FAN1 Nuclease bound to 5' hydroxyl (dT-dT) single flap DNA

4ric, resolution 2.80Å

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Structural highlights

4ric is a 8 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4ri8, 4ri9, 4ria, 4rib, 4rid
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

DNA interstrand cross-links (ICLs) are highly toxic lesions associated with cancer and degenerative diseases. ICLs can be repaired by the Fanconi anemia (FA) pathway and through FA-independent processes involving the FAN1 nuclease. In this work, FAN1-DNA crystal structures and biochemical data reveal that human FAN1 cleaves DNA successively at every third nucleotide. In vitro, this exonuclease mechanism allows FAN1 to excise an ICL from one strand through flanking incisions. DNA access requires a 5'-terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3' flap, suggesting that FAN1 action is coupled to DNA synthesis or recombination. FAN1's mechanism of ICL excision is well suited for processing other localized DNA adducts as well.

DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1.,Wang R, Persky NS, Yoo B, Ouerfelli O, Smogorzewska A, Elledge SJ, Pavletich NP Science. 2014 Nov 28;346(6213):1127-30. doi: 10.1126/science.1258973. PMID:25430771^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Wang R, Persky NS, Yoo B, Ouerfelli O, Smogorzewska A, Elledge SJ, Pavletich NP. DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1. Science. 2014 Nov 28;346(6213):1127-30. doi: 10.1126/science.1258973. PMID:25430771 doi:http://dx.doi.org/10.1126/science.1258973