2r8j

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Structure of the Eukaryotic DNA Polymerase eta in complex with 1,2-d(GpG)-cisplatin containing DNA

Structural highlights

2r8j is a 6 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.1Å
Ligands:CA, CPT, DCP
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

POLH_YEAST 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. Efficiently incorporates nucleotides opposite to other UV or oxidative DNA damages like O(6)-methylguanine, 7,8-dihydro-8-oxoguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine of 2'-deoxyguanosine (FaPydG), or p-benzoquinone DNA adducts.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]

Evolutionary Conservation

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

Publication Abstract from PubMed

DNA polymerase eta (Pol eta) is a eukaryotic lesion bypass polymerase that helps organisms to survive exposure to ultraviolet (UV) radiation, and tumor cells to gain resistance against cisplatin-based chemotherapy. It allows cells to replicate across cross-link lesions such as 1,2-d(GpG) cisplatin adducts (Pt-GG) and UV-induced cis-syn thymine dimers. We present structural and biochemical analysis of how Pol eta copies Pt-GG-containing DNA. The damaged DNA is bound in an open DNA binding rim. Nucleotidyl transfer requires the DNA to rotate into an active conformation, driven by hydrogen bonding of the templating base to the dNTP. For the 3'dG of the Pt-GG, this step is accomplished by a Watson-Crick base pair to dCTP and is biochemically efficient and accurate. In contrast, bypass of the 5'dG of the Pt-GG is less efficient and promiscuous for dCTP and dATP as a result of the presence of the rigid Pt cross-link. Our analysis reveals the set of structural features that enable Pol eta to replicate across strongly distorting DNA lesions.

Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta.,Alt A, Lammens K, Chiocchini C, Lammens A, Pieck JC, Kuch D, Hopfner KP, Carell T Science. 2007 Nov 9;318(5852):967-70. PMID:17991862[35]

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

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Citations
26 reviews cite this structure
Molecular mechanisms of cisplatin resistance.
Galluzzi et al. (2012)
25 more
98 other articles
No citations found

See Also

References

  1. ↑ McDonald JP, Levine AS, Woodgate R. The Saccharomyces cerevisiae RAD30 gene, a homologue of Escherichia coli dinB and umuC, is DNA damage inducible and functions in a novel error-free postreplication repair mechanism. Genetics. 1997 Dec;147(4):1557-68. PMID:9409821
  2. ↑ Johnson RE, Prakash S, Prakash L. Requirement of DNA polymerase activity of yeast Rad30 protein for its biological function. J Biol Chem. 1999 Jun 4;274(23):15975-7. PMID:10347143
  3. ↑ Washington MT, Johnson RE, Prakash S, Prakash L. Fidelity and processivity of Saccharomyces cerevisiae DNA polymerase eta. J Biol Chem. 1999 Dec 24;274(52):36835-8. PMID:10601233
  4. ↑ Johnson RE, Prakash S, Prakash L. Efficient bypass of a thymine-thymine dimer by yeast DNA polymerase, Poleta. Science. 1999 Feb 12;283(5404):1001-4. PMID:9974380
  5. ↑ Xiao W, Chow BL, Broomfield S, Hanna M. The Saccharomyces cerevisiae RAD6 group is composed of an error-prone and two error-free postreplication repair pathways. Genetics. 2000 Aug;155(4):1633-41. PMID:10924462
  6. ↑ Yuan F, Zhang Y, Rajpal DK, Wu X, Guo D, Wang M, Taylor JS, Wang Z. Specificity of DNA lesion bypass by the yeast DNA polymerase eta. J Biol Chem. 2000 Mar 17;275(11):8233-9. PMID:10713149
  7. ↑ Haracska L, Prakash S, Prakash L. Replication past O(6)-methylguanine by yeast and human DNA polymerase eta. Mol Cell Biol. 2000 Nov;20(21):8001-7. PMID:11027270
  8. ↑ Haracska L, Yu SL, Johnson RE, Prakash L, Prakash S. Efficient and accurate replication in the presence of 7,8-dihydro-8-oxoguanine by DNA polymerase eta. Nat Genet. 2000 Aug;25(4):458-61. PMID:10932195 doi:http://dx.doi.org/10.1038/78169
  9. ↑ Washington MT, Johnson RE, Prakash S, Prakash L. Accuracy of thymine-thymine dimer bypass by Saccharomyces cerevisiae DNA polymerase eta. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3094-9. PMID:10725365 doi:http://dx.doi.org/10.1073/pnas.050491997
  10. ↑ Minko IG, Washington MT, Prakash L, Prakash S, Lloyd RS. Translesion DNA synthesis by yeast DNA polymerase eta on templates containing N2-guanine adducts of 1,3-butadiene metabolites. J Biol Chem. 2001 Jan 26;276(4):2517-22. Epub 2000 Nov 2. PMID:11062246 doi:http://dx.doi.org/10.1074/jbc.M007867200
  11. ↑ Haracska L, Kondratick CM, Unk I, Prakash S, Prakash L. Interaction with PCNA is essential for yeast DNA polymerase eta function. Mol Cell. 2001 Aug;8(2):407-15. PMID:11545742
  12. ↑ Yu SL, Johnson RE, Prakash S, Prakash L. Requirement of DNA polymerase eta for error-free bypass of UV-induced CC and TC photoproducts. Mol Cell Biol. 2001 Jan;21(1):185-8. PMID:11113193 doi:http://dx.doi.org/10.1128/MCB.21.1.185-188.2001
  13. ↑ Kondratick CM, Washington MT, Prakash S, Prakash L. Acidic residues critical for the activity and biological function of yeast DNA polymerase eta. Mol Cell Biol. 2001 Mar;21(6):2018-25. PMID:11238937 doi:http://dx.doi.org/10.1128/MCB.21.6.2018-2025.2001
  14. ↑ Washington MT, Johnson RE, Prakash S, Prakash L. Mismatch extension ability of yeast and human DNA polymerase eta. J Biol Chem. 2001 Jan 19;276(3):2263-6. Epub 2000 Oct 27. PMID:11054429 doi:http://dx.doi.org/10.1074/jbc.M009049200
  15. ↑ Bresson A, Fuchs RP. Lesion bypass in yeast cells: Pol eta participates in a multi-DNA polymerase process. EMBO J. 2002 Jul 15;21(14):3881-7. PMID:12110599 doi:http://dx.doi.org/10.1093/emboj/cdf363
  16. ↑ Zhang H, Siede W. UV-induced T-->C transition at a TT photoproduct site is dependent on Saccharomyces cerevisiae polymerase eta in vivo. Nucleic Acids Res. 2002 Mar 1;30(5):1262-7. PMID:11861920
  17. ↑ Sun L, Zhang K, Zhou L, Hohler P, Kool ET, Yuan F, Wang Z, Taylor JS. Yeast pol eta holds a cis-syn thymine dimer loosely in the active site during elongation opposite the 3'-T of the dimer, but tightly opposite the 5'-T. Biochemistry. 2003 Aug 12;42(31):9431-7. PMID:12899630 doi:http://dx.doi.org/10.1021/bi0345687
  18. ↑ Johnson RE, Trincao J, Aggarwal AK, Prakash S, Prakash L. Deoxynucleotide triphosphate binding mode conserved in Y family DNA polymerases. Mol Cell Biol. 2003 Apr;23(8):3008-12. PMID:12665597
  19. ↑ Kozmin SG, Pavlov YI, Kunkel TA, Sage E. Roles of Saccharomyces cerevisiae DNA polymerases Poleta and Polzeta in response to irradiation by simulated sunlight. Nucleic Acids Res. 2003 Aug 1;31(15):4541-52. PMID:12888515
  20. ↑ Washington MT, Wolfle WT, Spratt TE, Prakash L, Prakash S. Yeast DNA polymerase eta makes functional contacts with the DNA minor groove only at the incoming nucleoside triphosphate. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5113-8. Epub 2003 Apr 11. PMID:12692307 doi:http://dx.doi.org/10.1073/pnas.0837578100
  21. ↑ Washington MT, Prakash L, Prakash S. Mechanism of nucleotide incorporation opposite a thymine-thymine dimer by yeast DNA polymerase eta. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12093-8. Epub 2003 Oct 3. PMID:14527996 doi:http://dx.doi.org/10.1073/pnas.2134223100
  22. ↑ Gu C, Wang Y. LC-MS/MS identification and yeast polymerase eta bypass of a novel gamma-irradiation-induced intrastrand cross-link lesion G[8-5]C. Biochemistry. 2004 Jun 1;43(21):6745-50. PMID:15157108 doi:http://dx.doi.org/10.1021/bi0497749
  23. ↑ Hwang H, Taylor JS. Role of base stacking and sequence context in the inhibition of yeast DNA polymerase eta by pyrene nucleotide. Biochemistry. 2004 Nov 23;43(46):14612-23. PMID:15544332 doi:http://dx.doi.org/10.1021/bi0489558
  24. ↑ Zhao B, Xie Z, Shen H, Wang Z. Role of DNA polymerase eta in the bypass of abasic sites in yeast cells. Nucleic Acids Res. 2004 Jul 29;32(13):3984-94. Print 2004. PMID:15284331 doi:http://dx.doi.org/10.1093/nar/gkh710
  25. ↑ McCulloch SD, Kokoska RJ, Chilkova O, Welch CM, Johansson E, Burgers PM, Kunkel TA. Enzymatic switching for efficient and accurate translesion DNA replication. Nucleic Acids Res. 2004 Aug 27;32(15):4665-75. Print 2004. PMID:15333698 doi:http://dx.doi.org/10.1093/nar/gkh777
  26. ↑ Niimi A, Limsirichaikul S, Yoshida S, Iwai S, Masutani C, Hanaoka F, Kool ET, Nishiyama Y, Suzuki M. Palm mutants in DNA polymerases alpha and eta alter DNA replication fidelity and translesion activity. Mol Cell Biol. 2004 Apr;24(7):2734-46. PMID:15024063
  27. ↑ Hwang H, Taylor JS. Evidence for Watson-Crick and not Hoogsteen or wobble base pairing in the selection of nucleotides for insertion opposite pyrimidines and a thymine dimer by yeast DNA pol eta. Biochemistry. 2005 Mar 29;44(12):4850-60. PMID:15779911 doi:http://dx.doi.org/10.1021/bi048244+
  28. ↑ Xie Z, Zhang Y, Guliaev AB, Shen H, Hang B, Singer B, Wang Z. The p-benzoquinone DNA adducts derived from benzene are highly mutagenic. DNA Repair (Amst). 2005 Dec 8;4(12):1399-409. Epub 2005 Sep 21. PMID:16181813 doi:http://dx.doi.org/S1568-7864(05)00215-6
  29. ↑ Gibbs PE, McDonald J, Woodgate R, Lawrence CW. The relative roles in vivo of Saccharomyces cerevisiae Pol eta, Pol zeta, Rev1 protein and Pol32 in the bypass and mutation induction of an abasic site, T-T (6-4) photoadduct and T-T cis-syn cyclobutane dimer. Genetics. 2005 Feb;169(2):575-82. Epub 2004 Nov 1. PMID:15520252 doi:http://dx.doi.org/genetics.104.034611
  30. ↑ Ober M, Muller H, Pieck C, Gierlich J, Carell T. Base pairing and replicative processing of the formamidopyrimidine-dG DNA lesion. J Am Chem Soc. 2005 Dec 28;127(51):18143-9. PMID:16366567 doi:http://dx.doi.org/10.1021/ja0549188
  31. ↑ Carlson KD, Washington MT. Mechanism of efficient and accurate nucleotide incorporation opposite 7,8-dihydro-8-oxoguanine by Saccharomyces cerevisiae DNA polymerase eta. Mol Cell Biol. 2005 Mar;25(6):2169-76. PMID:15743815 doi:http://dx.doi.org/25/6/2169
  32. ↑ Vu B, Cannistraro VJ, Sun L, Taylor JS. DNA synthesis past a 5-methylC-containing cis-syn-cyclobutane pyrimidine dimer by yeast pol eta is highly nonmutagenic. Biochemistry. 2006 Aug 1;45(30):9327-35. PMID:16866379 doi:http://dx.doi.org/10.1021/bi0602009
  33. ↑ Abdulovic AL, Jinks-Robertson S. The in vivo characterization of translesion synthesis across UV-induced lesions in Saccharomyces cerevisiae: insights into Pol zeta- and Pol eta-dependent frameshift mutagenesis. Genetics. 2006 Mar;172(3):1487-98. Epub 2005 Dec 30. PMID:16387871 doi:http://dx.doi.org/genetics.105.052480
  34. ↑ Zhao B, Wang J, Geacintov NE, Wang Z. Poleta, Polzeta and Rev1 together are required for G to T transversion mutations induced by the (+)- and (-)-trans-anti-BPDE-N2-dG DNA adducts in yeast cells. Nucleic Acids Res. 2006 Jan 13;34(2):417-25. Print 2006. PMID:16415180 doi:http://dx.doi.org/34/2/417
  35. ↑ Alt A, Lammens K, Chiocchini C, Lammens A, Pieck JC, Kuch D, Hopfner KP, Carell T. Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta. Science. 2007 Nov 9;318(5852):967-70. PMID:17991862 doi:318/5852/967

Contents


PDB ID 2r8j

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