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4eey

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Revision as of 17:23, 11 August 2016

Crystal structure of human DNA polymerase eta in ternary complex with a cisplatin DNA adduct

Structural highlights

4eey is a 3 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:	POLH, RAD30, RAD30A, XPV (HUMAN)
Activity:	DNA-directed DNA polymerase, with EC number 2.7.7.7
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]

Publication Abstract from PubMed

A major clinical problem in the use of cisplatin to treat cancers is tumor resistance. DNA polymerase eta (Pol-eta) is a crucial polymerase that allows cancer cells to cope with the cisplatin-DNA adducts that are formed during chemotherapy. We present here a structure of human Pol-eta inserting deoxycytidine triphosphate (dCTP) opposite a cisplatin intrastrand cross-link (PtGpG). We show that the specificity of human Pol-eta for PtGpG derives from an active site that is open to permit Watson-Crick geometry of the nascent PtGpG-dCTP base pair and to accommodate the lesion without steric hindrance. This specificity is augmented by the residues Gln38 and Ser62, which interact with PtGpG, and Arg61, which interacts with the incoming dCTP. Collectively, the structure provides a basis for understanding how Pol-eta in human cells can tolerate the DNA damage caused by cisplatin chemotherapy and offers a framework for the design of inhibitors in cancer therapy.

Structural basis for cisplatin DNA damage tolerance by human polymerase eta during cancer chemotherapy.,Ummat A, Rechkoblit O, Jain R, Roy Choudhury J, Johnson RE, Silverstein TD, Buku A, Lone S, Prakash L, Prakash S, Aggarwal AK Nat Struct Mol Biol. 2012 May 6;19(6):628-32. doi: 10.1038/nsmb.2295. PMID:22562137^[11]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Ummat A, Rechkoblit O, Jain R, Roy Choudhury J, Johnson RE, Silverstein TD, Buku A, Lone S, Prakash L, Prakash S, Aggarwal AK. Structural basis for cisplatin DNA damage tolerance by human polymerase eta during cancer chemotherapy. Nat Struct Mol Biol. 2012 May 6;19(6):628-32. doi: 10.1038/nsmb.2295. PMID:22562137 doi:10.1038/nsmb.2295

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4eey"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human DNA polymerase eta in ternary complex with a cisplatin DNA adduct==
 <StructureSection load='4eey' size='340' side='right' caption='[[4eey]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4eey]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EEY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EEY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4eey]] 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=4EEY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EEY FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CPT:CISPLATIN'>CPT</scene>, <scene name='pdbligand=DCP:2-DEOXYCYTIDINE-5-TRIPHOSPHATE'>DCP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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 Homo sapiens])</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=4eey FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eey OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eey RCSB], [http://www.ebi.ac.uk/pdbsum/4eey PDBsum]</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=4eey FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eey OCA], [http://pdbe.org/4eey PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4eey RCSB], [http://www.ebi.ac.uk/pdbsum/4eey PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4eey ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4eey" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 28: / Line 30: @@
 </StructureSection>
 [[Category: DNA-directed DNA polymerase]]
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Aggarwal, A K]]
 [[Category: Buku, A]]

4eey

From Proteopedia

Revision as of 17:23, 11 August 2016

Crystal structure of human DNA polymerase eta in ternary complex with a cisplatin DNA adduct

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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