| Structural highlights
4dl3 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: | 0KX, GOL, MG |
| Related: | 3mr2, 3mr3, 3mr5, 3mr6, 3si8, 4dl2, 4dl4, 4dl5, 4dl6, 4dl7 |
| 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
Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase eta (hPol eta). Here, we report crystal structures of hPol eta complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol eta is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol eta differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol eta undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol eta is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol eta is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance.
Structural basis of human DNA polymerase eta-mediated chemoresistance to cisplatin.,Zhao Y, Biertumpfel C, Gregory MT, Hua YJ, Hanaoka F, Yang W Proc Natl Acad Sci U S A. 2012 Apr 23. PMID:22529383[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Zhao Y, Biertumpfel C, Gregory MT, Hua YJ, Hanaoka F, Yang W. Structural basis of human DNA polymerase eta-mediated chemoresistance to cisplatin. Proc Natl Acad Sci U S A. 2012 Apr 23. PMID:22529383 doi:10.1073/pnas.1202681109
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