Impact of Chemical Adducts on Translesion Synthesis in Replicative and Bypass DNA Polymerases: From Structure to Function

Eoff, Robert L.; Egli, Martin; Guengerich, Peter

doi:10.1002/9783527630110.ch13

Cited by 10 publications

(9 citation statements)

References 209 publications

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“…The variation in potencies is most probably associated with the structural differences between adducts and the subsequent effects on removal by DNA repair mechanisms (Buterin et al 2000;Dreij et al 2005;Kropachev et al 2013;Suh et al 1995). However, it could also be a result of changes in DNA polymerase activity and incorrect base-pair insertion resulting from post-lesion DNA synthesis (Broyde et al 2010;Eoff et al 2010;Huang et al 2003).…”

Section: Carcinogenic Effects Of Pahsmentioning

confidence: 99%

Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment

Jarvis¹,

Dreij²,

Mattsson³

et al. 2014

Toxicology

150

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In this review we discuss the effects of exposure to complex PAH mixtures in vitro and in vivo on mechanisms related to carcinogenesis. Of particular concern regarding exposure to complex PAH mixtures is how interactions between different constituents can affect the carcinogenic response and how these might be included in risk assessment. Overall the findings suggest that the responses resulting from exposure to complex PAH mixtures is varied and complicated. More- and less-than additive effects on bioactivation and DNA damage formation have been observed depending on the various mixtures studied, and equally dependent on the different test systems that are used. Furthermore, the findings show that the commonly used biological end-point of DNA damage formation is insufficient for studying mixture effects. At present the assessment of the risk of exposure to complex PAH mixtures involves comparison to individual compounds using either a surrogate or a component-based potency approach. We discuss how future risk assessment strategies for complex PAH mixtures should be based around whole mixture assessment in order to account for interaction effects. Inherent to this is the need to incorporate different experimental approaches using robust and sensitive biological endpoints. Furthermore, the emphasis on future research should be placed on studying real life mixtures that better represent the complex PAH mixtures that humans are exposed to.

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Section: Carcinogenic Effects Of Pahsmentioning

confidence: 99%

Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment

Jarvis¹,

Dreij²,

Mattsson³

et al. 2014

Toxicology

150

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“…The kinetics of its mechanism have been studied extensively,36,37 including bypass of DNA adducts 38-43. Dpo444 is capable of bypass of various DNA adducts and has been investigated in considerable detail in terms of both its function45-49 and structure 50-52. In addition to these C2 modifications, we also changed the C6 oxo group of dG to sulfur (6-SdG; the nucleoside is a drug and has been studied previously regarding interactions with some DNA polymerases53-56).…”

Section: Introductionmentioning

confidence: 99%

Steric and Electrostatic Effects at the C2 Atom Substituent Influence Replication and Miscoding of the DNA Deamination Product Deoxyxanthosine and Analogs by DNA Polymerases

Zhang

Bren

Kozekov

et al. 2009

Journal of Molecular Biology

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Deoxyinosine (dI) and deoxyxanthosine (dX) are both formed in DNA at appreciable levels in vivo by deamination of deoxyadenosine (dA) and deoxyguanosine (dG), respectively, and can miscode. Structure-activity relationships for dA pairing have been examined extensively using analogs but relatively few studies have probed the roles of the individual hydrogen-bonding atoms of dG in DNA replication. The replicative bacteriophage T7 DNA polymerase/exonuclease− (pol T7−) and the translesion DNA polymerase Sulfolobus solfataricus pol IV (Dpo4) were used as models to discern the mechanisms of miscoding by DNA polymerases. Removal of the 2-amino group from the template dG (i.e., dI) had little impact on the catalytic efficiency of either polymerase, as judged by either steady-state or pre-steady-state kinetic analysis, although the misincorporation frequency was increased by an order of magnitude. dX was highly miscoding with both polymerases, and incorporation of several bases was observed. The addition of an electronegative fluorine atom at the 2-position of dI lowered the oligonucleotide Tm and strongly inhibited incorporation of dCTP. The addition of bromine or oxygen (dX) at C2 lowered the Tm further, strongly inhibited both polymerases, and increased the frequency of misincorporation. Linear activity models show the effects of oxygen (dX) and the halogens at C2 on both DNA polymerases as mainly due to a combination of both steric and electrostatic factors, producing a clash with the paired cytosine O2 atom, as opposed to either bulk or perturbation of purine ring electron density alone.

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“…Yfamily pols share the right-handed palm, finger, and thumb domains with replicative ones but feature an additional little finger domain and unique make-ups of their active sites. E. coli possesses five pols, with pols IV and V being members of the Y-Family (30). Humans have at least 19 pols, of which pols η, κ, and ι and REV1 belong to the Y-Family.…”

Section: Introductionmentioning

confidence: 99%

Enzymatic bypass and the structural basis of miscoding opposite the DNA adduct 1,N2-ethenodeoxyguanosine by human DNA translesion polymerase η

Ghodke

Mali

Patra

et al. 2021

Journal of Biological Chemistry

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Impact of Chemical Adducts on Translesion Synthesis in Replicative and Bypass DNA Polymerases: From Structure to Function

Cited by 10 publications

References 209 publications

Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment

Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment

Steric and Electrostatic Effects at the C2 Atom Substituent Influence Replication and Miscoding of the DNA Deamination Product Deoxyxanthosine and Analogs by DNA Polymerases

Enzymatic bypass and the structural basis of miscoding opposite the DNA adduct 1,N2-ethenodeoxyguanosine by human DNA translesion polymerase η

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