DNA Adducts from a Tumorigenic Metabolite of Benzo[a]pyrene Block Human RNA Polymerase II Elongation in a Sequence- and Stereochemistry-dependent Manner

Perlow, Rebecca A.; Kolbanovskii, Alexander; Hingerty, Brian E.; Geacintov, Nicholas E.; Broyde, Suse; Scicchitano, David A.

doi:10.1016/s0022-2836(02)00593-4

Cited by 62 publications

(95 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most forms of damage targeted for repair by TCR also impede the translocation of RNAP complexes along DNA templates in vitro (6,8,33,35,36). Because bacteria, yeast, and mammals possess TCR, this mechanism may be evolutionarily conserved for efficient repair of DNA modifications that threaten genomic stability.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II

Cline

Riggins

Tornaletti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

“…Thus far, RNAPII arrest has been most prominent at types of DNA damage that cause significant structural distortions in DNA (6,8,33,35,36). The bends induced in the helical axis by CPDs and cisplatin intrastrand crosslinks may resemble those found in natural pause sequences for RNAPs (38).…”

Section: Discussionmentioning

confidence: 99%

Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II

Cline

Riggins

Tornaletti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

“…Another challenge involves delineating connections between lesion impact on DNA polymerase function and lesion repair. Here, RNA polymerases provide a potential link: bulky lesions such as those derived from BP [51] cause RNA polymerase stalling, which invokes the transcription-coupled nucleotide excision repair (NER) machinery [52,53], but much remains to be learned about relationships between lesion structure and repair susceptibility by this machinery [54]. Understanding lesion-processing in cells will require the elucidation of concerted interactions between Y-family DNA polymerases with other polymerases and other components of the holoenzyme replication complex; the participation of other proteins such as the eukaryotic ubiquitylation machinery also must be further explicated [6,7,[55][56][57].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

Self Cite

View full text Add to dashboard Cite

When a high-fidelity DNA polymerase encounters certain DNA-damage sites, its progress can be stalled and one or more lesion-bypass polymerases are recruited to transit the lesion. Here, we consider two representative types of lesions: (i) 7,8-dihydro-8-oxogua-nine (8-oxoG), a small, highly prevalent lesion caused by oxidative damage; and (ii) bulky lesions derived from the environmental pre-carcinogen benzo [a]pyrene, in the high-fidelity DNA polymerase Bacillus fragment (BF) from Bacillus stearothermophilus and in the lesion-bypass DNA polymerase IV (Dpo4) from Sulfolobus solfataricus. The tight fit of the BF polymerase around the nascent base pair contrasts with the more spacious, solvent-exposed active site of Dpo4, and these differences in architecture result in distinctions in their respective functions: one-step versus stepwise polymerase translocation, mutagenic versus accurate bypass of 8-oxoG, and polymerase stalling versus mutagenic bypass at bulky benzo[a]pyrene-derived lesions. Lesions and DNA polymerasesUntil 1999, it was widely understood that bacteria have three DNA polymerases and mammals have five [1]. In 1999, however, an entirely new category of polymerases was discovered in prokaryotes and eukaryotes [2-4] -the lesion-bypass DNA polymerases. The function of lesion-bypass polymerases is to replicate past lesion-containing DNA templates in a process called translesion synthesis [5][6][7]. Now at least 16 DNA polymerases are known in eukaryotes [8] and five in bacteria [9]. Furthermore, since 1999, crystal structures of DNA polymerases, including those containing lesions, have provided new structural insights into the mechanistic aspects of translesion synthesis and polymerase stalling associated with DNA lesions. For a review of the structures and mechanisms of DNA polymerases up to the year 2005, see Ref.[10].Here, we discuss the structural and functional features of representative high-fidelity and lesion-bypass DNA polymerases (Box 1) and how these features affect the processing of certain forms of DNA damage. The lesions considered are derived from reactions of intermediates produced by endogenous sources or from the metabolic activation of environmental genotoxic

show abstract

“…Persistent bulky adducts in DNA block the progression of replicative DNA polymerases (26,27) and RNA polymerase II (28). DNA polymerase ␤ (Pol ␤), the smallest eukaryotic polymerase (39 kDa) belonging to the X-family of DNA polymerases, has been extensively characterized biologically, kinetically, dynamically, and structurally (for a recent review, see ref.…”

mentioning

confidence: 99%

Structure of DNA polymerase β with a benzo[ c ]phenanthrene diol epoxide-adducted template exhibits mutagenic features

Batra

Shock

Prasad

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We have determined the crystal structure of the human base excision repair enzyme DNA polymerase ␤ (Pol ␤) in complex with a 1-nt gapped DNA substrate containing a template N 2 -guanine adduct of the tumorigenic (؊)-benzo[c]phenanthrene 4R,3S-diol 2S,1R-epoxide in the gap. Nucleotide insertion opposite this adduct favors incorrect purine nucleotides over the correct dCMP and hence can be mutagenic. The structure reveals that the phenanthrene ring system is stacked with the base pair immediately 3 to the modified guanine, thereby occluding the normal binding site for the correct incoming nucleoside triphosphate. The modified guanine base is displaced downstream and prevents the polymerase from achieving the catalytically competent closed conformation. The incoming nucleotide binding pocket is distorted, and the adducted deoxyguanosine is in a syn conformation, exposing its Hoogsteen edge, which can hydrogen-bond with dATP or dGTP. In a reconstituted base excision repair system, repair of a deaminated cytosine (i.e., uracil) opposite the adducted guanine was dramatically decreased at the Pol ␤ insertion step, but not blocked. The efficiency of gap-filling dCMP insertion opposite the adduct was diminished by >6 orders of magnitude compared with an unadducted templating guanine. In contrast, significant misinsertion of purine nucleotides (but not dTMP) opposite the adducted guanine was observed. Pol ␤ also misinserts a purine nucleotide opposite the adduct with ungapped DNA and exhibits limited bypass DNA synthesis. These results indicate that Pol ␤-dependent base excision repair of uracil opposite, or replication through, this bulky DNA adduct can be mutagenic.DNA adduct ͉ DNA repair ͉ fidelity ͉ mutagenesis P olycyclic aromatic hydrocarbons (PAHs) such as benzo- , and the adduct derived from trans-opening of the epoxide ring by the exocyclic 2-amino group of guanine in DNA, which is the subject of the present investigation.Bulky PAH-derived lesions can persist in human tissues when cellular repair enzymes fail to correct these lesions (13). The presence of these lesions in the genome blocks replicative DNA polymerases. If these lesions are not repaired, they must be bypassed for replication to continue. Bypass DNA synthesis occurs when a translesional DNA polymerase is recruited to the site of DNA damage and inserts a nucleotide opposite the adduct. DNA synthesis can be error-free or error-prone. The resulting base pair is then extended by either the same DNA polymerase or an auxiliary polymerase. Because replication of these adducts is known to result in mutations (14-16), mutagenic bypass provides a mechanism for adduct-induced tumor initiation and progression.Several DNA repair mechanisms protect cells from the deleterious effects of DNA lesions. For example, bulky DNA adducts such as PAH adducts and the formamidopyrimidine adduct of aflatoxin are primarily repaired by nucleotide excision repair (17, 18), although some unstable B[a]P DE adducts might promote depurination and elicit the base excision repair (BER...

show abstract

DNA Adducts from a Tumorigenic Metabolite of Benzo[a]pyrene Block Human RNA Polymerase II Elongation in a Sequence- and Stereochemistry-dependent Manner

Cited by 62 publications

References 68 publications

Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II

Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Structure of DNA polymerase β with a benzo[ c ]phenanthrene diol epoxide-adducted template exhibits mutagenic features

Contact Info

Product

Resources

About