Hydrogen Bonding of 7,8-Dihydro-8-oxodeoxyguanosine with a Charged Residue in the Little Finger Domain Determines Miscoding Events in Sulfolobus solfataricus DNA Polymerase Dpo4

Eoff, Robert L.; Irimia, A.; Angel, Karen C.; Egli, Martin; Guengerich, F. Peter

doi:10.1074/jbc.m702290200

Cited by 72 publications

(95 citation statements)

References 43 publications

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“…The hydrogen-bonding network in the 8-oxoG structure is an indirect readout of the unique O8 atom of the 8-oxoG: the steric clash engendered by the O8 forces the backbone to rotate by ~180° around its O3′-P torsion, relocating it in a way that produces the observed hydrogen-bonding network. Analogous crystal structure studies using Dpo4 harboring Arg332 substitutions also support the view that a hydrogen bond between Arg332 and 8-oxoG helps in determining the high fidelity and efficiency of Dpo4-catalyzed bypass of this lesion [26]. The general principle emerges that a templating 8-oxoG residue within high-fidelity DNA polymerases, with their confined active sites, has a greater preference than that within Dpo4 for adopting the abnormal syn glycosidic bond conformation to alleviate the steric crowding.…”

Section: Dpo4 Bypasses 8-oxog Accuratelymentioning

confidence: 68%

“…Biochemical processing and X-ray crystal-lographic studies of DNA containing 8-oxoG in complexes with BF [25] and Dpo4 [14,26] have highlighted striking differences in how these polymerases cope with this oxidative guanine lesion. The high-fidelity DNA polymerase BF incorporates the mismatched dATP opposite the damaged base approximately ninefold more efficiently than it does the normal partner dCTP [25], whereas Dpo4 favors dCTP over dATP by > 100-fold [14].…”

Section: Small Lesion Processing: 8-oxog Bf Favors 8-oxog-a Mispairingmentioning

confidence: 99%

“…Likewise, X-ray crystallographic structures of Dpo4 in complex with DNA, both with and without dNTP have been determined (for example, see Refs [4,[13][14][15][16][17]). Crystal structures of lesion-containing complexes for these two polymerases are also available (for example, see Refs [14,[18][19][20][21][22][23][24][25][26][27]), which shed light on their contrasting mechanisms for processing damaged DNA templates. We consider two important DNA lesion prototypes as examples of small and bulky lesions, respectively: 7,8-dihydro-8-oxoguanine (8-oxoG; Box 2), a ubiquitous product of reactive oxygen species (ROS), and DNA adducts derived from a tumorigenic metabolite of the environmental pre-carcinogen benzo[a]pyrene (BP; Box 3).…”

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confidence: 99%

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Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

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When a high-fidelity DNA polymerase encounters certain DNA-damage sites, its progress can be stalled and one or more lesion-bypass polymerases are recruited to transit the lesion. Here, we consider two representative types of lesions: (i) 7,8-dihydro-8-oxogua-nine (8-oxoG), a small, highly prevalent lesion caused by oxidative damage; and (ii) bulky lesions derived from the environmental pre-carcinogen benzo [a]pyrene, in the high-fidelity DNA polymerase Bacillus fragment (BF) from Bacillus stearothermophilus and in the lesion-bypass DNA polymerase IV (Dpo4) from Sulfolobus solfataricus. The tight fit of the BF polymerase around the nascent base pair contrasts with the more spacious, solvent-exposed active site of Dpo4, and these differences in architecture result in distinctions in their respective functions: one-step versus stepwise polymerase translocation, mutagenic versus accurate bypass of 8-oxoG, and polymerase stalling versus mutagenic bypass at bulky benzo[a]pyrene-derived lesions. Lesions and DNA polymerasesUntil 1999, it was widely understood that bacteria have three DNA polymerases and mammals have five [1]. In 1999, however, an entirely new category of polymerases was discovered in prokaryotes and eukaryotes [2-4] -the lesion-bypass DNA polymerases. The function of lesion-bypass polymerases is to replicate past lesion-containing DNA templates in a process called translesion synthesis [5][6][7]. Now at least 16 DNA polymerases are known in eukaryotes [8] and five in bacteria [9]. Furthermore, since 1999, crystal structures of DNA polymerases, including those containing lesions, have provided new structural insights into the mechanistic aspects of translesion synthesis and polymerase stalling associated with DNA lesions. For a review of the structures and mechanisms of DNA polymerases up to the year 2005, see Ref.[10].Here, we discuss the structural and functional features of representative high-fidelity and lesion-bypass DNA polymerases (Box 1) and how these features affect the processing of certain forms of DNA damage. The lesions considered are derived from reactions of intermediates produced by endogenous sources or from the metabolic activation of environmental genotoxic

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Section: Dpo4 Bypasses 8-oxog Accuratelymentioning

confidence: 68%

Section: Small Lesion Processing: 8-oxog Bf Favors 8-oxog-a Mispairingmentioning

confidence: 99%

mentioning

confidence: 99%

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Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

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“…4B). In addition, Dpo4 is able to alter the syn/anti equilibrium by specifically interacting with the O 8 atom of anti 8-oxo-G (29). In contrast, polι replicates the 8-oxo-G lesion exclusively using the mutagenic Hoogsteen edge (Fig.…”

Section: Resultsmentioning

confidence: 98%

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

Kirouac

2011

Proc. Natl. Acad. Sci. U.S.A.

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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.DNA replication | Y family polymerase | translesion DNA synthesis | oxidative lesion | DNA mutagenesis

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“…However, we observed that the pol homolog Dpo4 from Sulfolobus solfataricus bypasses 8-oxoG with high fidelity (19:1 ratio of dCTP:dATP incorporation opposite 8-oxoG) and efficiency (pre-steady-state kinetics revealed faster rates of dCTP incorporation opposite 8-oxoG than G) (30) that could be attributed to a significant extent to Arg-332 from the LF domain (31). By comparison, we established that human pol (hpol ) bypasses 8-oxoG in an error-prone fashion, with dATP rather than dCTP preferentially incorporated opposite the lesion (32).…”

mentioning

confidence: 99%

Kinetics, Structure, and Mechanism of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Human DNA Polymerase η

Patra

Nagy

Zhang

et al. 2014

Journal of Biological Chemistry

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140

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Background: 8-OxoG is a major oxidative lesion in DNA and is associated with cancer. Results: Kinetic and mass spectrometric studies demonstrate that human polymerase bypasses 8-oxoG in a largely error-free manner. Conclusion: Arginine 61 from the finger domain plays a key role in error-free bypass at the insertion stage. Significance: In addition to photo-adducts and cisplatinated DNA, polymerase might also be involved in accurate bypass of 8-oxoG in vivo.

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Hydrogen Bonding of 7,8-Dihydro-8-oxodeoxyguanosine with a Charged Residue in the Little Finger Domain Determines Miscoding Events in Sulfolobus solfataricus DNA Polymerase Dpo4

Cited by 72 publications

References 43 publications

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

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

Kinetics, Structure, and Mechanism of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Human DNA Polymerase η

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