5dqh

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Crystal Structure of Human DNA Polymerase Eta Inserting dGMPNPP Opposite O4-EthylthymidineCrystal Structure of Human DNA Polymerase Eta Inserting dGMPNPP Opposite O4-Ethylthymidine

Structural highlights

5dqh 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.
Method:X-ray diffraction, Resolution 1.99Å
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]

Publication Abstract from PubMed

DNA lesions that elude repair may undergo translesion synthesis catalyzed by Y-family DNA polymerases. O(4)-Alkylthymidines, persistent adducts that can result from carcinogenic agents, may be encountered by DNA polymerases. The influence of lesion orientation around the C4-O(4) bond on processing by human DNA polymerase eta (hPol eta) was studied for oligonucleotides containing O(4)-methylthymidine, O(4)-ethylthymidine, and analogs restricting the O(4)-methylene group in an anti-orientation. Primer extension assays revealed that the O(4)-alkyl orientation influences hPol eta bypass. Crystal structures of hPol eta*DNA*dNTP ternary complexes with O(4)-methyl- or O(4)-ethylthymidine in the template strand showed the nucleobase of the former lodged near the ceiling of the active site, with the syn-O(4)-methyl group engaged in extensive hydrophobic interactions. This unique arrangement for O(4)-methylthymidine with hPol eta, inaccessible for the other analogs due to steric/conformational restriction, is consistent with differences observed for nucleotide incorporation and supports the concept that lesion conformation influences extension across DNA damage. Together, these results provide mechanistic insights on the mutagenicity of O(4)MedT and O(4)EtdT when acted upon by hPol eta.

Lesion Orientation of O(4)-Alkylthymidine Influences Replication by Human DNA Polymerase eta.,O'Flaherty DK, Patra A, Su Y, Guengerich FP, Egli M, Wilds CJ Chem Sci. 2016 Aug 1;7(8):4896-4904. doi: 10.1039/C6SC00666C. Epub 2016 Apr 26. PMID:27574558[11]

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

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
  11. ↑ O'Flaherty DK, Patra A, Su Y, Guengerich FP, Egli M, Wilds CJ. Lesion Orientation of O(4)-Alkylthymidine Influences Replication by Human DNA Polymerase eta. Chem Sci. 2016 Aug 1;7(8):4896-4904. doi: 10.1039/C6SC00666C. Epub 2016 Apr 26. PMID:27574558 doi:http://dx.doi.org/10.1039/C6SC00666C

5dqh, resolution 1.99Å

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