| Structural highlights
3mfh is a 3 chain structure with sequence from Atcc 18824. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| NonStd Res: | |
| Related: | 1jih, 3mfi |
| Gene: | RAD30, DBH1, YDR419W (ATCC 18824) |
| Activity: | DNA-directed DNA polymerase, with EC number 2.7.7.7 |
| 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 (Poleta) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Poleta (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Poleta (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Poleta to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis for Poleta's action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans.
Structural basis for the suppression of skin cancers by DNA polymerase eta.,Silverstein TD, Johnson RE, Jain R, Prakash L, Prakash S, Aggarwal AK Nature. 2010 Jun 24;465(7301):1039-43. PMID:20577207[35]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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+
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Silverstein TD, Johnson RE, Jain R, Prakash L, Prakash S, Aggarwal AK. Structural basis for the suppression of skin cancers by DNA polymerase eta. Nature. 2010 Jun 24;465(7301):1039-43. PMID:20577207 doi:10.1038/nature09104
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