Elucidating Structure–Function Relationships in Bulky DNA Lesions: From Solution Structures to Polymerases

Broyde, Suse; Wang, Lihua; Patel, Dinshaw J.; Geacintov, Nicholas E.

doi:10.1002/9783527630110.ch14

Cited by 3 publications

(1 citation statement)

References 105 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

View full text Add to dashboard Cite

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Site‐Specific N²‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass

Ghodke

Pradeepkumar

2020

Eur J Org Chem

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The N2‐position of deoxyguanosine (dG) in DNA is susceptible to modification by various damaging agents. These modifications (lesions or adducts) can stall the DNA replication by replicative polymerases, and if the common DNA repair pathways do not remove them, it can result in genomic instability. This generally leads to the death or oncogenic transformation of the cell. An important mechanism to deal with this problem is Translesion synthesis (TLS), a bypass mechanism, which involves the tolerance of DNA damage by low‐fidelity DNA polymerases (TLS polymerases). To understand the accuracy of TLS polymerases, a chemical biology approach is required. In this review, we discuss the reliable methods to synthesize specific N2‐dG DNA adducts and how they are tolerated by bacterial TLS polymerase Pol IV and its mammalian orthologue hpol κ. Molecular insights on the accurate bypass of these adducts emerge from the primer extension assays, X‐ray crystallographic, and molecular modeling studies are reviewed here.

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C8-Linked Bulky Guanosine DNA Adducts: Experimental And Computational Insights Into Adduct Conformational Preferences And Resulting Mutagenicity

2012

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Bulky DNA adducts are formed through the covalent attachment of aryl groups to the DNA nucleobases. Many of these adducts are known to possess conformational heterogeneity, which is responsible for the variety of mutagenic outcomes associated with these lesions. The present contribution reviews several conformational and mutagenic themes that are prevalent among the DNA adducts formed at the C8-site of the guanine nucleobase. The most important conclusions obtained (to date) from experiments are summarized including the anti/syn conformational preference of the adducts, their potential to inflict DNA mutations and mismatch stabilization, and their interactions with DNA polymerases and repair enzymes. Additionally, the unique role that computer calculations can play in understanding the structural properties of these adducts are highlighted.

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Elucidating Structure–Function Relationships in Bulky DNA Lesions: From Solution Structures to Polymerases

Cited by 3 publications

References 105 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

Site‐Specific N²‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass

C8-Linked Bulky Guanosine DNA Adducts: Experimental And Computational Insights Into Adduct Conformational Preferences And Resulting Mutagenicity

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Elucidating Structure–Function Relationships in Bulky DNA Lesions: From Solution Structures to Polymerases

Cited by 3 publications

References 105 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

Site‐Specific N2‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass

C8-Linked Bulky Guanosine DNA Adducts: Experimental And Computational Insights Into Adduct Conformational Preferences And Resulting Mutagenicity

Contact Info

Product

Resources

About

Site‐Specific N²‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass