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==Human DNA polymerase eta - DNA ternary complex with the 3'T of a CPD in the active site (TT1)==
==Human DNA polymerase eta - DNA ternary complex with the 3'T of a CPD in the active site (TT1)==
<StructureSection load='3mr3' size='340' side='right' caption='[[3mr3]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
<StructureSection load='3mr3' size='340' side='right'caption='[[3mr3]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3mr3]] 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=3MR3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MR3 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3mr3]] is a 3 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=3MR3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MR3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DZ4:2-DEOXY-5-O-[(R)-HYDROXY{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]AMINO}PHOSPHORYL]ADENOSINE'>DZ4</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.75&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TTD:CIS-SYN+CYCLOBUTANE+THYMINE+DIMER'>TTD</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DZ4:2-DEOXY-5-O-[(R)-HYDROXY{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]AMINO}PHOSPHORYL]ADENOSINE'>DZ4</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TTD:CIS-SYN+CYCLOBUTANE+THYMINE+DIMER'>TTD</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3mr2|3mr2]], [[3mr4|3mr4]], [[3mr5|3mr5]], [[3mr6|3mr6]]</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=3mr3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mr3 OCA], [https://pdbe.org/3mr3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mr3 RCSB], [https://www.ebi.ac.uk/pdbsum/3mr3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mr3 ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POLH, RAD30, RAD30A, XPV ([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=3mr3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mr3 OCA], [http://pdbe.org/3mr3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3mr3 RCSB], [http://www.ebi.ac.uk/pdbsum/3mr3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3mr3 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/POLH_HUMAN POLH_HUMAN]] Defects in POLH are the cause of xeroderma pigmentosum variant type (XPV) [MIM:[http://omim.org/entry/278750 278750]]; also designated as XP-V. Xeroderma pigmentosum (XP) is an autosomal recessive disease due to deficient nucleotide excision repair. It is characterized by hypersensitivity of the skin to sunlight, followed by high incidence of skin cancer and frequent neurologic abnormalities. XPV shows normal nucleotide excision repair, but an exaggerated delay in recovery of replicative DNA synthesis. Most XPV patients do not develop clinical symptoms and skin neoplasias until a later age. Clinical manifestations are limited to photo-induced deterioration of the skin and eyes.<ref>PMID:10385124</ref> <ref>PMID:10398605</ref> <ref>PMID:11032022</ref> <ref>PMID:11121129</ref> <ref>PMID:11773631</ref>
[https://www.uniprot.org/uniprot/POLH_HUMAN POLH_HUMAN] Defects in POLH are the cause of xeroderma pigmentosum variant type (XPV) [MIM:[https://omim.org/entry/278750 278750]; also designated as XP-V. Xeroderma pigmentosum (XP) is an autosomal recessive disease due to deficient nucleotide excision repair. It is characterized by hypersensitivity of the skin to sunlight, followed by high incidence of skin cancer and frequent neurologic abnormalities. XPV shows normal nucleotide excision repair, but an exaggerated delay in recovery of replicative DNA synthesis. Most XPV patients do not develop clinical symptoms and skin neoplasias until a later age. Clinical manifestations are limited to photo-induced deterioration of the skin and eyes.<ref>PMID:10385124</ref> <ref>PMID:10398605</ref> <ref>PMID:11032022</ref> <ref>PMID:11121129</ref> <ref>PMID:11773631</ref>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/POLH_HUMAN POLH_HUMAN]] 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. Plays an important role in the repair of UV-induced pyrimidine dimers. Depending on the context, it inserts the correct base, but causes frequent base transitions and transversions. May play a role in hypermutation at immunoglobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity. Targets POLI to replication foci.<ref>PMID:10385124</ref> <ref>PMID:11743006</ref> <ref>PMID:11376341</ref> <ref>PMID:14630940</ref> <ref>PMID:14734526</ref>
[https://www.uniprot.org/uniprot/POLH_HUMAN POLH_HUMAN] 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. Plays an important role in the repair of UV-induced pyrimidine dimers. Depending on the context, it inserts the correct base, but causes frequent base transitions and transversions. May play a role in hypermutation at immunoglobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity. Targets POLI to replication foci.<ref>PMID:10385124</ref> <ref>PMID:11743006</ref> <ref>PMID:11376341</ref> <ref>PMID:14630940</ref> <ref>PMID:14734526</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3mr3 ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3mr3 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase eta (Poleta), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Poleta at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Poleta acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Poleta orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Poleta missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Poleta in replicating through D loop and DNA fragile sites.
Structure and mechanism of human DNA polymerase eta.,Biertumpfel C, Zhao Y, Kondo Y, Ramon-Maiques S, Gregory M, Lee JY, Masutani C, Lehmann AR, Hanaoka F, Yang W Nature. 2010 Jun 24;465(7301):1044-8. PMID:20577208<ref>PMID:20577208</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3mr3" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[DNA polymerase|DNA polymerase]]
*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: DNA-directed DNA polymerase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Biertumpfel, C]]
[[Category: Biertumpfel C]]
[[Category: Gregory, M T]]
[[Category: Gregory MT]]
[[Category: Lee, J Y]]
[[Category: Lee JY]]
[[Category: Ramon-Maiques, S]]
[[Category: Ramon-Maiques S]]
[[Category: Yang, W]]
[[Category: Yang W]]
[[Category: Zhao, Y]]
[[Category: Zhao Y]]
[[Category: Cpd]]
[[Category: Dna damage]]
[[Category: Pol eta]]
[[Category: Polymerase]]
[[Category: Thymine dimer]]
[[Category: Transferase-dna complex]]
[[Category: Xeroderma pigmentosum variant]]
[[Category: Xpv]]

Latest revision as of 13:26, 21 February 2024

Human DNA polymerase eta - DNA ternary complex with the 3'T of a CPD in the active site (TT1)Human DNA polymerase eta - DNA ternary complex with the 3'T of a CPD in the active site (TT1)

Structural highlights

3mr3 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.75Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

POLH_HUMAN Defects in POLH are the cause of xeroderma pigmentosum variant type (XPV) [MIM:278750; also designated as XP-V. Xeroderma pigmentosum (XP) is an autosomal recessive disease due to deficient nucleotide excision repair. It is characterized by hypersensitivity of the skin to sunlight, followed by high incidence of skin cancer and frequent neurologic abnormalities. XPV shows normal nucleotide excision repair, but an exaggerated delay in recovery of replicative DNA synthesis. Most XPV patients do not develop clinical symptoms and skin neoplasias until a later age. Clinical manifestations are limited to photo-induced deterioration of the skin and eyes.[1] [2] [3] [4] [5]

Function

POLH_HUMAN 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. Plays an important role in the repair of UV-induced pyrimidine dimers. Depending on the context, it inserts the correct base, but causes frequent base transitions and transversions. May play a role in hypermutation at immunoglobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity. Targets POLI to replication foci.[6] [7] [8] [9] [10]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature. 1999 Jun 17;399(6737):700-4. PMID:10385124 doi:10.1038/21447
  2. ↑ Johnson RE, Kondratick CM, Prakash S, Prakash L. hRAD30 mutations in the variant form of xeroderma pigmentosum. Science. 1999 Jul 9;285(5425):263-5. PMID:10398605
  3. ↑ Yuasa M, Masutani C, Eki T, Hanaoka F. Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene. Oncogene. 2000 Sep 28;19(41):4721-8. PMID:11032022 doi:10.1038/sj.onc.1203842
  4. ↑ Itoh T, Linn S, Kamide R, Tokushige H, Katori N, Hosaka Y, Yamaizumi M. Xeroderma pigmentosum variant heterozygotes show reduced levels of recovery of replicative DNA synthesis in the presence of caffeine after ultraviolet irradiation. J Invest Dermatol. 2000 Dec;115(6):981-5. PMID:11121129 doi:10.1046/j.1523-1747.2000.00154.x
  5. ↑ Broughton BC, Cordonnier A, Kleijer WJ, Jaspers NG, Fawcett H, Raams A, Garritsen VH, Stary A, Avril MF, Boudsocq F, Masutani C, Hanaoka F, Fuchs RP, Sarasin A, Lehmann AR. Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):815-20. Epub 2002 Jan 2. PMID:11773631 doi:10.1073/pnas.022473899
  6. ↑ Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature. 1999 Jun 17;399(6737):700-4. PMID:10385124 doi:10.1038/21447
  7. ↑ Glick E, Vigna KL, Loeb LA. Mutations in human DNA polymerase eta motif II alter bypass of DNA lesions. EMBO J. 2001 Dec 17;20(24):7303-12. PMID:11743006 doi:10.1093/emboj/20.24.7303
  8. ↑ Zeng X, Winter DB, Kasmer C, Kraemer KH, Lehmann AR, Gearhart PJ. DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol. 2001 Jun;2(6):537-41. PMID:11376341 doi:10.1038/88740
  9. ↑ 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
  10. ↑ Faili A, Aoufouchi S, Weller S, Vuillier F, Stary A, Sarasin A, Reynaud CA, Weill JC. DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination. J Exp Med. 2004 Jan 19;199(2):265-70. PMID:14734526 doi:10.1084/jem.20031831

3mr3, resolution 1.75Å

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