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5um9

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Revision as of 09:30, 4 December 2019

Flap endonuclease 1 (FEN1) D86N with 5'-flap substrate DNA and Sm3+

Structural highlights

5um9 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	FEN1, RAD2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FEN1_HUMAN] Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.

Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability.,Tsutakawa SE, Thompson MJ, Arvai AS, Neil AJ, Shaw SJ, Algasaier SI, Kim JC, Finger LD, Jardine E, Gotham VJB, Sarker AH, Her MZ, Rashid F, Hamdan SM, Mirkin SM, Grasby JA, Tainer JA Nat Commun. 2017 Jun 27;8:15855. doi: 10.1038/ncomms15855. PMID:28653660^[7]

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

References

↑ Robins P, Pappin DJ, Wood RD, Lindahl T. Structural and functional homology between mammalian DNase IV and the 5'-nuclease domain of Escherichia coli DNA polymerase I. J Biol Chem. 1994 Nov 18;269(46):28535-8. PMID:7961795
↑ Shen B, Nolan JP, Sklar LA, Park MS. Essential amino acids for substrate binding and catalysis of human flap endonuclease 1. J Biol Chem. 1996 Apr 19;271(16):9173-6. PMID:8621570
↑ Tom S, Henricksen LA, Bambara RA. Mechanism whereby proliferating cell nuclear antigen stimulates flap endonuclease 1. J Biol Chem. 2000 Apr 7;275(14):10498-505. PMID:10744741
↑ Qiu J, Bimston DN, Partikian A, Shen B. Arginine residues 47 and 70 of human flap endonuclease-1 are involved in DNA substrate interactions and cleavage site determination. J Biol Chem. 2002 Jul 5;277(27):24659-66. Epub 2002 May 1. PMID:11986308 doi:http://dx.doi.org/10.1074/jbc.M111941200
↑ Guo Z, Qian L, Liu R, Dai H, Zhou M, Zheng L, Shen B. Nucleolar localization and dynamic roles of flap endonuclease 1 in ribosomal DNA replication and damage repair. Mol Cell Biol. 2008 Jul;28(13):4310-9. doi: 10.1128/MCB.00200-08. Epub 2008 Apr, 28. PMID:18443037 doi:http://dx.doi.org/10.1128/MCB.00200-08
↑ Guo Z, Zheng L, Xu H, Dai H, Zhou M, Pascua MR, Chen QM, Shen B. Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nat Chem Biol. 2010 Oct;6(10):766-73. doi: 10.1038/nchembio.422. Epub 2010 Aug, 22. PMID:20729856 doi:http://dx.doi.org/10.1038/nchembio.422
↑ Tsutakawa SE, Thompson MJ, Arvai AS, Neil AJ, Shaw SJ, Algasaier SI, Kim JC, Finger LD, Jardine E, Gotham VJB, Sarker AH, Her MZ, Rashid F, Hamdan SM, Mirkin SM, Grasby JA, Tainer JA. Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability. Nat Commun. 2017 Jun 27;8:15855. doi: 10.1038/ncomms15855. PMID:28653660 doi:http://dx.doi.org/10.1038/ncomms15855

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5um9"

@@ Line 1: / Line 1: @@
 ==Flap endonuclease 1 (FEN1) D86N with 5'-flap substrate DNA and Sm3+==
-<StructureSection load='5um9' size='340' side='right' caption='[[5um9]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
+<StructureSection load='5um9' size='340' side='right'caption='[[5um9]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5um9]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UM9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UM9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5um9]] is a 4 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=5UM9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UM9 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <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">FEN1, RAD2 ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5um9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5um9 OCA], [http://pdbe.org/5um9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5um9 RCSB], [http://www.ebi.ac.uk/pdbsum/5um9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5um9 ProSAT]</span></td></tr>
 </table>
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 5um9" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Endonuclease 3D structures|Endonuclease 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Arvai, A S]]
 [[Category: Tainer, J A]]

5um9

From Proteopedia

Revision as of 09:30, 4 December 2019

Flap endonuclease 1 (FEN1) D86N with 5'-flap substrate DNA and Sm3+

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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