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==Base pairing mechanism of N2,3-ethenoguanine with dCTP by human polymerase iota==
==Base pairing mechanism of N2,3-ethenoguanine with dCTP by human polymerase iota==
<StructureSection load='4fs2' size='340' side='right' caption='[[4fs2]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
<StructureSection load='4fs2' size='340' side='right'caption='[[4fs2]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4fs2]] is a 3 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=4FS2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FS2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4fs2]] is a 3 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=4FS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FS2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DCP:2-DEOXYCYTIDINE-5-TRIPHOSPHATE'>DCP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DCP:2-DEOXYCYTIDINE-5-TRIPHOSPHATE'>DCP</scene>, <scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene>, <scene name='pdbligand=EFG:1-(2-DEOXY-2-FLUORO-5-O-PHOSPHONO-BETA-D-ARABINOFURANOSYL)-1H-IMIDAZO[2,1-B]PURIN-4(5H)-ONE'>EFG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene>, <scene name='pdbligand=EFG:1-(2-DEOXY-2-FLUORO-5-O-PHOSPHONO-BETA-D-ARABINOFURANOSYL)-1H-IMIDAZO[2,1-B]PURIN-4(5H)-ONE'>EFG</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=4fs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fs2 OCA], [https://pdbe.org/4fs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fs2 RCSB], [https://www.ebi.ac.uk/pdbsum/4fs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fs2 ProSAT]</span></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3osn|3osn]], [[3v6h|3v6h]], [[3v6j|3v6j]], [[3v6k|3v6k]], [[4fs1|4fs1]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POLI, RAD30B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </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=4fs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fs2 OCA], [http://pdbe.org/4fs2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fs2 RCSB], [http://www.ebi.ac.uk/pdbsum/4fs2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fs2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/POLI_HUMAN POLI_HUMAN]] Error-prone DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunogobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity.<ref>PMID:11013228</ref> <ref>PMID:11251121</ref> <ref>PMID:11387224</ref> <ref>PMID:12410315</ref> <ref>PMID:14630940</ref> <ref>PMID:15199127</ref> <ref>PMID:15254543</ref>
[https://www.uniprot.org/uniprot/POLI_HUMAN POLI_HUMAN] Error-prone DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunogobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity.<ref>PMID:11013228</ref> <ref>PMID:11251121</ref> <ref>PMID:11387224</ref> <ref>PMID:12410315</ref> <ref>PMID:14630940</ref> <ref>PMID:15199127</ref> <ref>PMID:15254543</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</div>
</div>
<div class="pdbe-citations 4fs2" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 4fs2" style="background-color:#fffaf0;"></div>
==See Also==
*[[DNA polymerase|DNA polymerase]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: DNA-directed DNA polymerase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Zhao, L]]
[[Category: Synthetic construct]]
[[Category: 2'-fluoro arabinose]]
[[Category: Zhao L]]
[[Category: 3-ethenoguanine]]
[[Category: Dna polymerase]]
[[Category: Dna replication]]
[[Category: Dttp]]
[[Category: Human dna polymerase iota]]
[[Category: Lesion bypass]]
[[Category: N2]]
[[Category: Template]]
[[Category: Transferase-dna complex]]

Revision as of 23:08, 19 October 2022

Base pairing mechanism of N2,3-ethenoguanine with dCTP by human polymerase iotaBase pairing mechanism of N2,3-ethenoguanine with dCTP by human polymerase iota

Structural highlights

4fs2 is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

POLI_HUMAN Error-prone DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunogobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity.[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

N2,3-Ethenoguanine (N2,3-epsilonG) is one of the exocyclic DNA adducts produced by endogenous processes (e.g., lipid peroxidation) and exposure to bioactivated vinyl monomers such as vinyl chloride, which is a known human carcinogen. Existing studies exploring the miscoding potential of this lesion are quite indirect due to the lability of the glycosidic bond. We utilized a 2'-fluoro isostere approach to stabilize this lesion and synthesized oligonucleotides containing 2'-fluoro-N2,3-epsilon-2'-deoxyarabinoguanosine to investigate the miscoding potential of N2,3-epsilonG by Y-family human DNA polymerases (pols). In primer extension assays, pol eta and pol kappa replicated through N2,3-epsilonG, whereas pol iota and REV1 yielded only one-base incorporation. Steady-state kinetics revealed that dCTP incorporation is preferred opposite N2,3-epsilonG, with relative efficiencies in the order of pol kappa > REV1 > pol eta approximately pol iota, and dTTP misincorporation is the major miscoding event by all four Y-family human DNA pols. Pol iota had the highest dTTP misincorporation frequency (0.71), followed by pol eta (0.63). REV1 misincorporated dTTP and dGTP with much lower frequencies. Crystal structures of pol iota with N2,3-epsilonG paired to dCTP and dTTP revealed Hoogsteen-like base pairing mechanisms. Two hydrogen bonds were observed in the N2,3-epsilonG:dCTP base pair, whereas only one appears to be present in the case of the N2,3-epsilonG:dTTP pair. Base pairing mechanisms derived from the crystal structures explain the slightly favored dCTP insertion for pol iota in steady-state kinetic analysis. Taken together, these results provide a basis for the mutagenic potential of N2,3-epsilonG.

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases.,Zhao L, Pence MG, Christov PP, Wawrzak Z, Choi JY, Rizzo CJ, Egli M, Guengerich FP J Biol Chem. 2012 Aug 21. PMID:22910910[8]

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

References

  1. ↑ Tissier A, Frank EG, McDonald JP, Iwai S, Hanaoka F, Woodgate R. Misinsertion and bypass of thymine-thymine dimers by human DNA polymerase iota. EMBO J. 2000 Oct 2;19(19):5259-66. PMID:11013228 doi:http://dx.doi.org/10.1093/emboj/19.19.5259
  2. ↑ Bebenek K, Tissier A, Frank EG, McDonald JP, Prasad R, Wilson SH, Woodgate R, Kunkel TA. 5'-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro. Science. 2001 Mar 16;291(5511):2156-9. PMID:11251121 doi:http://dx.doi.org/10.1126/science.1058386
  3. ↑ Frank EG, Tissier A, McDonald JP, Rapic-Otrin V, Zeng X, Gearhart PJ, Woodgate R. Altered nucleotide misinsertion fidelity associated with poliota-dependent replication at the end of a DNA template. EMBO J. 2001 Jun 1;20(11):2914-22. PMID:11387224 doi:http://dx.doi.org/10.1093/emboj/20.11.2914
  4. ↑ Faili A, Aoufouchi S, Flatter E, Gueranger Q, Reynaud CA, Weill JC. Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota. Nature. 2002 Oct 31;419(6910):944-7. PMID:12410315 doi:http://dx.doi.org/10.1038/nature01117
  5. ↑ Haracska L, Prakash L, Prakash S. A mechanism for the exclusion of low-fidelity human Y-family DNA polymerases from base excision repair. Genes Dev. 2003 Nov 15;17(22):2777-85. PMID:14630940 doi:10.1101/gad.1146103
  6. ↑ Washington MT, Minko IG, Johnson RE, Wolfle WT, Harris TM, Lloyd RS, Prakash S, Prakash L. Efficient and error-free replication past a minor-groove DNA adduct by the sequential action of human DNA polymerases iota and kappa. Mol Cell Biol. 2004 Jul;24(13):5687-93. PMID:15199127 doi:http://dx.doi.org/10.1128/MCB.24.13.5687-5693.2004
  7. ↑ Nair DT, Johnson RE, Prakash S, Prakash L, Aggarwal AK. Replication by human DNA polymerase-iota occurs by Hoogsteen base-pairing. Nature. 2004 Jul 15;430(6997):377-80. PMID:15254543 doi:10.1038/nature02692
  8. ↑ Zhao L, Pence MG, Christov PP, Wawrzak Z, Choi JY, Rizzo CJ, Egli M, Guengerich FP. Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases. J Biol Chem. 2012 Aug 21. PMID:22910910 doi:http://dx.doi.org/10.1074/jbc.M112.403253

4fs2, resolution 2.05Å

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