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6d0m

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Revision as of 10:02, 4 December 2019

Polymerase Eta post-insertion binary complex with cytarabine (AraC)

Structural highlights

6d0m 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:
NonStd Res:
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

Cytarabine (AraC) is an essential chemotherapeutic for acute myeloid leukemia (AML) and resistance to this drug is a major cause of treatment failure. AraC is a nucleoside analog that differs from 2'-deoxycytidine only by the presence of an additional hydroxyl group at the C2' position of the 2'-deoxyribose. The active form of the drug AraC 5'-triphosphate (AraCTP) is utilized by human replicative DNA polymerases to insert AraC at the 3' terminus of a growing DNA chain. This impedes further primer extension and is a primary basis for the drug action. The Y-family translesion synthesis (TLS) DNA polymerase eta (Poleta) counteracts this barrier to DNA replication by efficient extension from AraC-terminated primers. Here, we provide high-resolution structures of human Poleta with AraC incorporated at the 3'-primer terminus. We show that Poleta can accommodate AraC at different stages of the catalytic cycle, and that it can manipulate the conformation of the AraC sugar via specific hydrogen bonding and stacking interactions. Taken together, the structures provide a basis for the ability of Poleta to extend DNA synthesis from AraC terminated primers.

Structural basis for polymerase eta-promoted resistance to the anticancer nucleoside analog cytarabine.,Rechkoblit O, Choudhury JR, Buku A, Prakash L, Prakash S, Aggarwal AK Sci Rep. 2018 Aug 23;8(1):12702. doi: 10.1038/s41598-018-30796-w. PMID:30140014^[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
↑ Rechkoblit O, Choudhury JR, Buku A, Prakash L, Prakash S, Aggarwal AK. Structural basis for polymerase eta-promoted resistance to the anticancer nucleoside analog cytarabine. Sci Rep. 2018 Aug 23;8(1):12702. doi: 10.1038/s41598-018-30796-w. PMID:30140014 doi:http://dx.doi.org/10.1038/s41598-018-30796-w

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/6d0m"

@@ Line 1: / Line 1: @@
 ==Polymerase Eta post-insertion binary complex with cytarabine (AraC)==
-<StructureSection load='6d0m' size='340' side='right' caption='[[6d0m]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
+<StructureSection load='6d0m' size='340' side='right'caption='[[6d0m]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6d0m]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D0M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D0M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6d0m]] 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=6D0M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D0M FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAR:CYTOSINE+ARABINOSE-5-PHOSPHATE'>CAR</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 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=6d0m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d0m OCA], [http://pdbe.org/6d0m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d0m RCSB], [http://www.ebi.ac.uk/pdbsum/6d0m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d0m ProSAT]</span></td></tr>
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 6d0m" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
 == References ==
 <references/>
@@ Line 27: / Line 31: @@
 </StructureSection>
 [[Category: DNA-directed DNA polymerase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Aggarwal, A K]]
 [[Category: Rechkoblit, O]]

6d0m

From Proteopedia

Revision as of 10:02, 4 December 2019

Polymerase Eta post-insertion binary complex with cytarabine (AraC)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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