Recognition and Removal of Bulky DNA Lesions by the Nucleotide Excision Repair System

Cai, Yuqin; Kropachev, Konstantin; Kolbanovskiy, Marina; Kolbanovskiy, Alexander; Broyde, Suse; Patel, Dinshaw J.; Geacintov, Nicholas E.

doi:10.1002/9783527630110.ch12

Cited by 13 publications

(15 citation statements)

References 124 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…116 Therefore, the structural features of these forms of DNA damage and their relationships to DNA repair are of considerable interest. Examples of such structural studies are summarized in this section.…”

Section: Structural Features Of Bulky Pah–dna Adductsmentioning

confidence: 99%

Repair-Resistant DNA Lesions

Geacintov

Broyde

2017

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

The eukaryotic global genomic nucleotide excision repair (GG-NER) pathway is the major mechanism that removes most bulky and some nonbulky lesions from cellular DNA. There is growing evidence that certain DNA lesions are repaired slowly or are entirely resistant to repair in cells, tissues, and in cell extract model assay systems. It is well established that the eukaryotic DNA lesion-sensing proteins do not detect the damaged nucleotide, but recognize the distortions/destabilizations in the native DNA structure caused by the damaged nucleotides. In this article, the nature of the structural features of certain bulky DNA lesions that render them resistant to NER, or cause them to be repaired slowly, is compared to that of those that are good-to-excellent NER substrates. Understanding the structural features that distinguish NER-resistant DNA lesions from good NER substrates may be useful for interpreting the biological significance of biomarkers of exposure of human populations to genotoxic environmental chemicals. NER-resistant lesions can survive to replication and cause mutations that can initiate cancer and other diseases. Furthermore, NER diminishes the efficacy of certain chemotherapeutic drugs, and the design of more potent pharmaceuticals that resist repair can be advanced through a better understanding of the structural properties of DNA lesions that engender repair-resistance.

show abstract

Section: Structural Features Of Bulky Pah–dna Adductsmentioning

confidence: 99%

Repair-Resistant DNA Lesions

Geacintov

Broyde

2017

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The chemical structures of the DNA lesions, the base sequence contexts in which the lesions are embedded, as well as their stereochemical properties can affect the DNA repair efficiencies catalyzed by prokaryotic [6–12] and eukaryotic [4, 5, 13–16] repair systems. While the importance of these factors on NER efficiencies is well documented, the exact molecular origins underlying these differences are still not well understood [17]. …”

Section: Introductionmentioning

confidence: 99%

Probing for DNA damage with β-hairpins: Similarities in incision efficiencies of bulky DNA adducts by prokaryotic and human nucleotide excision repair systems in vitro

et al. 2011

Self Cite

View full text Add to dashboard Cite

Nucleotide excision repair (NER) is an important prokaryotic and eukaryotic defense mechanism that removes a large variety of structurally distinct lesions in cellular DNA. While the proteins involved are completely different, the mode of action of these two repair systems is similar, involving a cut-and-patch mechanism in which an oligonucleotide sequence containing the lesion is excised. The prokaryotic and eukaryotic NER damage-recognition factors have common structural features of β-hairpin intrusion between the two DNA strands at the site of the lesion. In the present study, we explored the hypothesis that this common β-hairpin intrusion motif is mirrored in parallel NER incision efficiencies in the two systems. We have utilized human HeLa cell extracts and the prokaryotic UvrABC proteins to determine their relative NER incision efficiencies. We report here comparisons of relative NER efficiencies with a set of stereoisomeric DNA lesions derived from metabolites of benzo[a]pyrene and equine estrogens in different sequence contexts, utilizing 21 samples. We found a general qualitative trend towards similar relative NER incision efficiencies for ~ 65% of these substrates; the other cases deviate mostly by ~ 30% or less from a perfect correlation, although several more distant outliers are also evident. This resemblance is consistent with the hypothesis that lesion recognition through β-hairpin insertion, a common feature of the two systems, is facilitated by local thermodynamic destabilization induced by the lesions in both cases. In the case of the UvrABC system, varying the nature of the UvrC endonuclease, while maintaining the same UvrA/B proteins, can markedly affect the relative incision efficiencies. These observations suggest that, in addition to recognition involving the initial modified duplexes, downstream events involving UvrC can also play a role in distinguishing and processing different lesions in prokaryotic NER.

show abstract

“…If unrepaired the stable, bulky DNA lesions can lead to mutation by aberrant translesional bypass synthesis. 80 NER and translesional bypass polymerase reactions have yet to be performed with either estrogen- o -quinone DNA adducts or PAH o -quinone–DNA adducts. This work has lagged behind because of either the lack of elucidation of the relevant stereoisomeric structures of the adducts or the difficulty in synthesizing adducts in oligonucleotides that match those formed in cells.…”

Section: Covalent Quinone-dna Adducts Repair and Mutagenesismentioning

confidence: 99%

Genotoxicity of ortho-quinones: reactive oxygen species versus covalent modification

Penning

2017

Toxicol. Res.

View full text Add to dashboard Cite

o-Quinones are formed metabolically from natural and synthetic estrogens as well as upon exposure to polycyclic aromatic hydrocarbons (PAH) and contribute to estrogen and PAH carcinogenesis by genotoxic mechanisms. These mechanisms include the production of reactive oxygen species to produce DNA strand breaks and oxidatively damaged nucleobases; and the formation of covalent depurinating and stable DNA adducts. Unrepaired DNA-lesions can lead to mutation in critical growth control genes and cellular transformation. The genotoxicity of the o-quinones is exacerbated by nuclear translocation of estrogen o-quinones by the estrogen receptor and by the nuclear translocation of PAH o-quinones by the aryl hydrocarbon receptor. The properties of o-quinones, their formation and detoxication mechanisms, quinone-mediated DNA lesions and their mutagenic properties support an important role in hormonal and chemical carcinogenesis.

show abstract

Recognition and Removal of Bulky DNA Lesions by the Nucleotide Excision Repair System

Cited by 13 publications

References 124 publications

Repair-Resistant DNA Lesions

Repair-Resistant DNA Lesions

Probing for DNA damage with β-hairpins: Similarities in incision efficiencies of bulky DNA adducts by prokaryotic and human nucleotide excision repair systems in vitro

Genotoxicity of ortho-quinones: reactive oxygen species versus covalent modification

Contact Info

Product

Resources

About