The effect of DNA damage on the formation of protein/DNA complexes

Parsian, Azemat J.; Funk, Margo C.; Tao, Ting Y.; Hunt, Clayton R.

doi:10.1016/s0027-5107(02)00016-7

Cited by 17 publications

(11 citation statements)

References 19 publications

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“…The biological significance of the observed inhibition of DNA–protein interaction and the downstream effects has been largely unexplored. Our observation that presence of both CPD and (6‐4) PD in the consensus binding site of transcription factor NF‐κB inhibits recombinant p50 binding is consistent with reports in the literature [6–10] that show that numerous types of DNA damage inhibit DNA–protein interactions. Although this is true of many transcription factors and types of damage a closer examination shows that the relationship may be more complex.…”

Section: Discussionsupporting

confidence: 92%

“…UV photoproducts such as CPD and (6‐4) PD also inhibit binding of the sequence‐specific transcription factors E2F, NF‐Y, AP‐1, and p53. O 6 ‐Methylguanine, nitrogen mustard and quinacrine mustard modifications have all been found to inhibit the binding of transcription factors to DNA [6–10]. On the other hand, the presence of bulky benzo[ a ]pyrene diol epoxide (BPDE) adducts in a TATA promoter sequence has been shown to enhance binding of the TATA binding protein [11].…”

Section: Introductionmentioning

confidence: 99%

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Ultraviolet radiation‐induced DNA damage in promoter elements inhibits gene expression

Ghosh¹,

Tummala²,

Mitchell³

2003

FEBS Letters

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Repair of DNA damage in gene promoters is slower than in actively transcribed genes. Persistent damage in gene promoters though transient can have signi¢cant biological effects on regulated gene expression. In this study we investigated the e¡ect of ultraviolet radiation on gene promoter-associated functions when DNA damage is located within and outside transcription factor binding sites. Our results show that both cyclobutane pyrimidine dimers and (6-4) photoproducts inhibit DNAp rotein interaction, in vitro transcript production and transactivation of reporter genes. The biological signi¢cance of transient DNA damage as a mechanism in carcinogenesis is discussed.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Ultraviolet radiation‐induced DNA damage in promoter elements inhibits gene expression

Ghosh¹,

Tummala²,

Mitchell³

2003

FEBS Letters

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“…It is noteworthy that RPA binding was unaffected by the presence of a single AP site in ssDNA, particularly because other DNA-binding proteins, such as sequence-specific transcription factors and telomere repeat binding proteins, have been shown to be adversely impacted by the presence of oxidative lesions, including abasic damage (44,45). Related to this topic, prior work has shown that RPA complex stability with ss adducted DNA is largely dependent on the nature of the DNA modification, where certain bulky lesions can negatively impact RPA binding affinity (46 -49).…”

Section: Discussionmentioning

confidence: 99%

Nucleotide Sequence and DNA Secondary Structure, as Well as Replication Protein A, Modulate the Single-stranded Abasic Endonuclease Activity of APE1

Fan

Matsumoto

Wilson

2006

Journal of Biological Chemistry

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A major role of the multifunctional human Ape1 protein is to incise at apurinic/apyrimidinic (AP) sites in DNA via site-specific endonuclease activity. This nuclease function has been well characterized on double-stranded (ds) DNA substrates, where the complementary strand provides a template for subsequent base excision repair events. Recently, Ape1 was found to incise efficiently at AP sites positioned within the single-stranded (ss) regions of various biologically relevant DNA configurations. The studies within indicated that the ss endonuclease activity of Ape1 is poorly active on ss AP site-containing polyadenine or polythymine oligonucleotides, suggesting a requirement for some form of DNA secondary structure for efficient cleavage. Apurinic/apyrimidinic (AP)2 endonuclease 1 (Ape1) is the major mammalian repair protein for abasic sites in DNA (1). This enzyme catalyzes incision of the phosphodiester backbone immediately 5Ј to an AP lesion, initiating a cascade of events that involves components of the base excision repair (BER) pathway and aims to remove the abasic residue and re-establish genetic integrity (2). Abasic sites are common products in DNA, arising either spontaneously (at a rate of 10,000 events per mammalian genome per day), via accelerated base release because of chemical modification, or through enzyme (glycosylase)-catalyzed removal of a damaged base (3, 4). If unrepaired, AP lesions present mutagenic and cytotoxic challenges to the cell (5). Deficiencies in Ape1 activity in mice have been associated with increased spontaneous mutation frequencies in both somatic and germ line cells (6), as well as increased cancer susceptibility and reduced survival in the face of exogenous oxidizing agents (7). It is noteworthy that, although uncommon, human Ape1 protein variants with reduced function have been identified (8).It is generally accepted that Ape1 is the predominant AP site incision enzyme in mammals, accounting for Ͼ95% (if not all) of the total cellular AP endonuclease activity (9). In fact, recent evidence argues that its AP endonuclease function is essential for cell viability (10, 11). For many years, this activity had been characterized on double-stranded (ds) AP-DNA substrates (12-14), as it was presumed that a successful BER event would take place exclusively on a template-containing (instructional) duplex DNA molecule. Recently, however, it was shown that Ape1 exhibits a robust endonuclease activity at AP sites in single-stranded (ss) oligonucleotides, in some instances greater than in dsDNA, as well as in several complex and biologically relevant ss structures, such as primertemplate duplexes, bubble conformations, and fork-like arrangements (15, 16). Presently, little is known about how these more "exotic" activities of Ape1 are modulated or how the resulting incision products are handled by the cell.Replication protein A (RPA) is the most abundant ssDNA-binding protein in mammalian cells, present at roughly 100,000 molecules per cell (17). This heterotrimeric complex was origina...

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“…7. Modified bases not only affect transcriptional integrity and replication but also DNA-protein binding (8,9). Consequently, oxidative DNA base damage is normally removed and repaired by the efficient base excision repair (BER) pathway system of prokaryotic and eukaryotic cells (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

Estimating the Effect of Human Base Excision Repair Protein Variants on the Repair of Oxidative DNA Base Damage

Sokhansanj

Wilson²

2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Epidemiologic studies have revealed a complex association between human genetic variance and cancer risk. Quantitative biological modeling based on experimental data can play a critical role in interpreting the effect of genetic variation on biochemical pathways relevant to cancer development and progression. Defects in human DNA base excision repair (BER) proteins can reduce cellular tolerance to oxidative DNA base damage caused by endogenous and exogenous sources, such as exposure to toxins and ionizing radiation. If not repaired, DNA base damage leads to cell dysfunction and mutagenesis, consequently leading to cancer, disease, and aging. Population screens have identified numerous single-nucleotide polymorphism variants in many BER proteins and some have been purified and found to exhibit mild kinetic defects. Epidemiologic studies have led to conflicting conclusions on the association between single-nucleotide polymorphism variants in BER proteins and cancer risk. Using experimental data for cellular concentration and the kinetics of normal and variant BER proteins, we apply a previously developed and tested human BER pathway model to (i) estimate the effect of mild variants on BER of abasic sites and 8-oxoguanine, a prominent oxidative DNA base modification, (ii) identify ranges of variation associated with substantial BER capacity loss, and (iii) reveal nonintuitive consequences of multiple simultaneous variants. Our findings support previous work suggesting that mild BER variants have a minimal effect on pathway capacity whereas more severe defects and simultaneous variation in several BER proteins can lead to inefficient repair and potentially deleterious consequences of cellular damage. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1000 -8)

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The effect of DNA damage on the formation of protein/DNA complexes

Cited by 17 publications

References 19 publications

Ultraviolet radiation‐induced DNA damage in promoter elements inhibits gene expression

Ultraviolet radiation‐induced DNA damage in promoter elements inhibits gene expression

Nucleotide Sequence and DNA Secondary Structure, as Well as Replication Protein A, Modulate the Single-stranded Abasic Endonuclease Activity of APE1

Estimating the Effect of Human Base Excision Repair Protein Variants on the Repair of Oxidative DNA Base Damage

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