Repair of exocyclic DNA adducts: rings of complexity

Hang, Bo

doi:10.1002/bies.20130

Cited by 32 publications

(25 citation statements)

References 98 publications

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“…The so-called bulky DNA adducts are formed by the covalent binding of those chemical carcinogens with large size, such as PAHs and aromatic amines, to various sites on DNA bases. These adducts also include exocyclic DNA bases such as the etheno, propano, and benzetheno adducts formed by respective bifunctional compounds [33, 34]. These bulky adducts represent a major and important class of DNA damage originating from exposure to cigarette smoke.…”

Section: Introductionmentioning

confidence: 99%

“…One characteristic of these bulky adducts is that they tend to significantly disrupt the DNA helical structure and block Watson-Crick base pairing [35, 36]. They are usually highly mutagenic, as exemplified by the PAH-DNA adducts [30] and exocyclic DNA adducts [34, 37]. Some of them may not be repaired (e.g., benzo[c]phenanthrene N 6 -dA adducts [38]) or only poorly repaired (e.g., two dibenzo[a,l]pyrene-induced DNA adduct [39]), thus leading to their persistence in genomic DNA.…”

Section: Introductionmentioning

confidence: 99%

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Formation and Repair of Tobacco Carcinogen‐Derived Bulky DNA Adducts

Hang

2010

Journal of Nucleic Acids

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DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N-nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O6-alkylguanine DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made in the areas concerning formation and repair of bulky DNA adducts in the context of tobacco carcinogen-associated genotoxic and carcinogenic effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Formation and Repair of Tobacco Carcinogen‐Derived Bulky DNA Adducts

Hang

2010

Journal of Nucleic Acids

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“…Acrolein mainly forms exocyclic adducts to DNA (9), mostly at guanine residues -1,N 2 -α-hydroxypropanoguanine and 1,N 2 -γ-hydroxypropanoguanine (HPGs) (10). The C5 cytosine methylation at CpG sequences greatly enhances the ACR-dG adduction at those sites.…”

Section: Introductionmentioning

confidence: 99%

1,N6-α-hydroxypropanoadenine, the acrolein adduct to adenine, is a substrate for AlkB dioxygenase

Dylewska

Kuśmierek

Pilżys

et al. 2017

Biochemical Journal

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SummaryCombination of in vivo, in vitro and in silico studies shows that acrolein adduct to adenine is mutagenic and is effectively repaired by AlkB dioxygenase. Cationic form of R isomer of HPA is strongly favored in AlkB active centre. -α-hydroxypropanoadenine (HPA) is an exocyclic DNA adduct of acrolein -an environmental pollutant and endocellular oxidative stress product. E. coli AlkB dioxygenase belongs to the superfamily of α-ketoglutarate (αKG)-and iron-dependent dioxygenases which remove alkyl lesions from bases via an oxidative mechanism, thereby restoring native DNA structure. Here, we provide in vivo and in vitro evidence that HPA is mutagenic and is effectively repaired by AlkB dioxygenase. HPA generated in plasmid DNA caused A→C and A→T transversions and, less frequently, A→G transitions. The lesion was efficiently repaired by purified AlkB protein; the optimal pH, Fe(II) and αKG concentrations for this reaction were determinated. In vitro kinetic data show that the protonated form of HPA is preferentially repaired by AlkB, albeit the reaction is stereoselective. Moreover, the number of reaction cycles carried out by an AlkB molecule remains limited. Molecular modeling of the T(HPA)T/AlkB complex demonstrated that the R stereoisomer in the equatorial conformation of the HPA hydroxyl group is strongly preferred, while the S one seems to be susceptible to AlkB-directed oxidative hydroxylation only when HPA adopts the syn conformation around the glycosidic bond. In addition to the biochemical activity assays, substrate binding to the protein was monitored by differential scanning fluorimetry allowing 2

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“…Uracil-DNA glycosylase (UNG) is the primary BER enzyme which excises uracil from DNA and is one of the most specific and efficient glycosylases in the BER pathway20. UNG also recognizes variety of other lesions212223, and has been shown to prevent viral integration of HIV1 in human cells24.…”

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Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation

Gokey

Hang

Guliaev

2016

Sci Rep

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Toxic metals are known to inhibit DNA repair but the underlying mechanisms of inhibition are still not fully understood. DNA repair enzymes such as human uracil-DNA glycosylase (hUNG) perform the initial step in the base excision repair (BER) pathway. In this work, we showed that cadmium [Cd(II)], a known human carcinogen, inhibited all activity of hUNG at 100 μM. Computational analyses based on 2 μs equilibrium, 1.6 μs steered molecular dynamics (SMD), and QM/MM MD determined that Cd(II) ions entered the enzyme active site and formed close contacts with both D145 and H148, effectively replacing the catalytic water normally found in this position. Geometry refinement by density functional theory (DFT) calculations showed that Cd(II) formed a tetrahedral structure with D145, P146, H148, and one water molecule. This work for the first time reports Cd(II) inhibition of hUNG which was due to replacement of the catalytic water by binding the active site D145 and H148 residues. Comparison of the proposed metal binding site to existing structural data showed that D145:H148 followed a general metal binding motif favored by Cd(II). The identified motif offered structural insights into metal inhibition of other DNA repair enzymes and glycosylases.

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Repair of exocyclic DNA adducts: rings of complexity

Cited by 32 publications

References 98 publications

Formation and Repair of Tobacco Carcinogen‐Derived Bulky DNA Adducts

Formation and Repair of Tobacco Carcinogen‐Derived Bulky DNA Adducts

1,N6-α-hydroxypropanoadenine, the acrolein adduct to adenine, is a substrate for AlkB dioxygenase

Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation

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