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Unique active site promotes error-free replication opposite an 8-oxo-guanine lesion by human DNA polymerase iota.

Kirouac KN, Ling H
Proc Natl Acad Sci U S A 108 3210-5 (2011)
Related entries: 3q8q, 3q8r

Cited: 38 times
EuropePMC logo PMID: 21300901

Abstract

The 8-oxo-guanine (8-oxo-G) lesion is the most abundant and mutagenic oxidative DNA damage existing in the genome. Due to its dual coding nature, 8-oxo-G causes most DNA polymerases to misincorporate adenine. Human Y-family DNA polymerase iota (polι) preferentially incorporates the correct cytosine nucleotide opposite 8-oxo-G. This unique specificity may contribute to polι's biological role in cellular protection against oxidative stress. However, the structural basis of this preferential cytosine incorporation is currently unknown. Here we present four crystal structures of polι in complex with DNA containing an 8-oxo-G lesion, paired with correct dCTP or incorrect dATP, dGTP, and dTTP nucleotides. An exceptionally narrow polι active site restricts the purine bases in a syn conformation, which prevents the dual coding properties of 8-oxo-G by inhibiting syn/anti conformational equilibrium. More importantly, the 8-oxo-G base in a syn conformation is not mutagenic in polι because its Hoogsteen edge does not form a stable base pair with dATP in the narrow active site. Instead, the syn 8-oxo-G template base forms the most stable replicating base pair with correct dCTP due to its small pyrimidine base size and enhanced hydrogen bonding with the Hoogsteen edge of 8-oxo-G. In combination with site directed mutagenesis, we show that Gln59 in the finger domain specifically interacts with the additional O(8) atom of the lesion base, which influences nucleotide selection, enzymatic efficiency, and replication stalling at the lesion site. Our work provides the structural mechanism of high-fidelity 8-oxo-G replication by a human DNA polymerase.

Reviews - 3q8p mentioned but not cited (1)

  1. DNA polymerases provide a canon of strategies for translesion synthesis past oxidatively generated lesions. Zahn KE, Wallace SS, Doublié S. Curr. Opin. Struct. Biol. 21 358-369 (2011)

Articles - 3q8p mentioned but not cited (1)

  1. Unique active site promotes error-free replication opposite an 8-oxo-guanine lesion by human DNA polymerase iota. Kirouac KN, Ling H. Proc. Natl. Acad. Sci. U.S.A. 108 3210-3215 (2011)


Reviews citing this publication (9)

  1. Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Sale JE, Lehmann AR, Woodgate R. Nat. Rev. Mol. Cell Biol. 13 141-152 (2012)
  2. Translesion DNA synthesis and mutagenesis in eukaryotes. Sale JE. Cold Spring Harb Perspect Biol 5 a012708 (2013)
  3. An overview of Y-Family DNA polymerases and a case study of human DNA polymerase η. Yang W. Biochemistry 53 2793-2803 (2014)
  4. Translesion DNA polymerases in eukaryotes: what makes them tick? Vaisman A, Woodgate R. Crit. Rev. Biochem. Mol. Biol. 52 274-303 (2017)
  5. The roles of DNA polymerase ζ and the Y family DNA polymerases in promoting or preventing genome instability. Sharma S, Helchowski CM, Canman CE. Mutat. Res. 743-744 97-110 (2013)
  6. Regulation of translesion DNA synthesis: Posttranslational modification of lysine residues in key proteins. McIntyre J, Woodgate R. DNA Repair (Amst.) 29 166-179 (2015)
  7. Structure of human DNA polymerase iota and the mechanism of DNA synthesis. Makarova AV, Kulbachinskiy AV. Biochemistry Mosc. 77 547-561 (2012)
  8. Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism. Yang W, Gao Y. Annu. Rev. Biochem. 87 239-261 (2018)
  9. Quantification and mapping of DNA modifications. Dai Y, Yuan BF, Feng YQ. RSC Chem Biol 2 1096-1114 (2021)

Articles citing this publication (27)

  1. A historical account of Hoogsteen base-pairs in duplex DNA. Nikolova EN, Zhou H, Gottardo FL, Alvey HS, Kimsey IJ, Al-Hashimi HM. Biopolymers 99 955-968 (2013)
  2. DNA polymerase minor groove interactions modulate mutagenic bypass of a templating 8-oxoguanine lesion. Freudenthal BD, Beard WA, Wilson SH. Nucleic Acids Res. 41 1848-1858 (2013)
  3. Structure and mechanism of error-free replication past the major benzo[a]pyrene adduct by human DNA polymerase κ. Jha V, Bian C, Xing G, Ling H. Nucleic Acids Res. 44 4957-4967 (2016)
  4. The steric gate of DNA polymerase ι regulates ribonucleotide incorporation and deoxyribonucleotide fidelity. Donigan KA, McLenigan MP, Yang W, Goodman MF, Woodgate R. J. Biol. Chem. 289 9136-9145 (2014)
  5. Ubiquitin mediates the physical and functional interaction between human DNA polymerases η and ι. McIntyre J, Vidal AE, McLenigan MP, Bomar MG, Curti E, McDonald JP, Plosky BS, Ohashi E, Woodgate R. Nucleic Acids Res. 41 1649-1660 (2013)
  6. Biochemical analysis of six genetic variants of error-prone human DNA polymerase ι involved in translesion DNA synthesis. Kim J, Song I, Jo A, Shin JH, Cho H, Eoff RL, Guengerich FP, Choi JY. Chem. Res. Toxicol. 27 1837-1852 (2014)
  7. The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice. Iguchi M, Osanai M, Hayashi Y, Koentgen F, Lee GH. Oncogene 33 3612-3617 (2014)
  8. Characterizing Watson-Crick versus Hoogsteen Base Pairing in a DNA-Protein Complex Using Nuclear Magnetic Resonance and Site-Specifically 13C- and 15N-Labeled DNA. Zhou H, Sathyamoorthy B, Stelling A, Xu Y, Xue Y, Pigli YZ, Case DA, Rice PA, Al-Hashimi HM. Biochemistry 58 1963-1974 (2019)
  9. Reactive Oxygen Species Play an Important Role in the Bactericidal Activity of Quinolone Antibiotics. Kottur J, Nair DT. Angew. Chem. Int. Ed. Engl. 55 2397-2400 (2016)
  10. Replication of the 2,6-diamino-4-hydroxy-N(5)-(methyl)-formamidopyrimidine (MeFapy-dGuo) adduct by eukaryotic DNA polymerases. Christov PP, Yamanaka K, Choi JY, Takata K, Wood RD, Guengerich FP, Lloyd RS, Rizzo CJ. Chem. Res. Toxicol. 25 1652-1661 (2012)
  11. A transposon-derived DNA polymerase from Entamoeba histolytica displays intrinsic strand displacement, processivity and lesion bypass. Pastor-Palacios G, López-Ramírez V, Cardona-Felix CS, Brieba LG. PLoS ONE 7 e49964 (2012)
  12. Roles of the active site residues and metal cofactors in noncanonical base-pairing during catalysis by human DNA polymerase iota. Makarova AV, Ignatov A, Miropolskaya N, Kulbachinskiy A. DNA Repair (Amst.) 22 67-76 (2014)
  13. The Werner syndrome protein limits the error-prone 8-oxo-dG lesion bypass activity of human DNA polymerase kappa. Maddukuri L, Ketkar A, Eddy S, Zafar MK, Eoff RL. Nucleic Acids Res. 42 12027-12040 (2014)
  14. A nucleotide-analogue-induced gain of function corrects the error-prone nature of human DNA polymerase iota. Ketkar A, Zafar MK, Banerjee S, Marquez VE, Egli M, Eoff RL. J. Am. Chem. Soc. 134 10698-10705 (2012)
  15. A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG. Burak MJ, Guja KE, Hambardjieva E, Derkunt B, Garcia-Diaz M. EMBO J. 35 2045-2059 (2016)
  16. Repair and translesion synthesis of O 6-alkylguanine DNA lesions in human cells. Du H, Wang P, Li L, Wang Y. J Biol Chem 294 11144-11153 (2019)
  17. Three Human Pol ι Variants with Impaired Polymerase Activity Fail to Rescue H2O2 Sensitivity in POLI-Deficient Cells. Yeom M, Hong JK, Kim JK, Guengerich FP, Choi JY. Chem Res Toxicol 33 2120-2129 (2020)
  18. Non-bulky Lesions in Human DNA: the Ways of Formation, Repair, and Replication. Ignatov AV, Bondarenko KA, Makarova AV. Acta Naturae 9 12-26 (2017)
  19. Association of POL1, MALT1, MC4R, PHLPP and DSEL single nucleotide polymorphisms in chromosome 18q region with type 2 diabetes in Tunisians. Turki A, Mahjoub T, Mtiraoui N, Abdelhedi M, Frih A, Almawi WY. Gene 527 243-247 (2013)
  20. DNA ligase I fidelity mediates the mutagenic ligation of pol β oxidized and mismatch nucleotide insertion products in base excision repair. Kamble P, Hall K, Chandak M, Tang Q, Çağlayan M. J Biol Chem 296 100427 (2021)
  21. Dynamic basis for dA•dGTP and dA•d8OGTP misincorporation via Hoogsteen base pairs. Gu S, Szymanski ES, Rangadurai AK, Shi H, Liu B, Manghrani A, Al-Hashimi HM. Nat Chem Biol 19 900-910 (2023)
  22. Comment Poli: Shining light on repair of oxidative DNA lesions and mutations. Kirouac KN, Ling H. Cell Cycle 10 1520-1521 (2011)
  23. "Mirror" Method to Estimate Mutagenic Activity of DNA Lesions. Gening LV, Shevchenko OV, Kazachenko KY, Tarantul VZ. Methods Protoc 1 (2018)
  24. DNA polymerase ι is acetylated in response to SN2 alkylating agents. McIntyre J, Sobolewska A, Fedorowicz M, McLenigan MP, Macias M, Woodgate R, Sledziewska-Gojska E. Sci Rep 9 4789 (2019)
  25. Estimation of the Mutagenic Potential of 8-Oxog in Nuclear Extracts of Mouse Cells Using the "Framed Mirror" Method. Gening LV, Volodin AA, Kazachenko KY, Makarova IV, Tarantul VZ. Methods Protoc 3 (2020)
  26. Location analysis of 8-oxo-7,8-dihydroguanine in DNA by polymerase-mediated differential coding. Tang F, Liu S, Li QY, Yuan J, Li L, Wang Y, Yuan BF, Feng YQ. Chem Sci 10 4272-4281 (2019)
  27. Mouse DNA polymerase ι lacking the forty-two amino acids encoded by exon-2 is catalytically inactive in vitro. Frank EG, McDonald JP, Yang W, Woodgate R. DNA Repair (Amst.) 50 71-76 (2017)


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