Interactions of Carcinogen-Bound DNA with Individual DNA Polymerases

Guengerich, F. Peter

doi:10.1021/cr0404693

Cited by 101 publications

(117 citation statements)

References 267 publications

(927 reference statements)

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“…The process, however, is interupted significantly when a damaged base is present in the template. Continued replication of the adduct-containing template is termed as translesion synthesis (TLS), which is a major source of point mutations (27,28). The TLS events are modulated by various factors including the lesion-induced conformational changes of the template, its surrounding base sequence context, and by the nature of DNA polymerases (28,29).…”

Section: And N-(2′-deoxyguanosin-8-yl)-2-aminofluorene (Af)mentioning

confidence: 99%

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Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Meneni¹,

Liang²,

Cho³

2007

Journal of Molecular Biology

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SUMMARYAdduct-induced conformational heterogeneity complicates the understanding of how DNA adducts exert mutation. A case in point is the N-deacetylated AF lesion [N-(2′-deoxyguanosin-8-yl)-2-aminofluorene], the major adduct derived from the strong liver carcinogen N-acetyl-2-aminofluorene. Three conformational families have been previously characterized and are dependent on the positioning of the aminofluorene rings: B is in the 'B-DNA' major groove, S is 'stacked' into the helix with base-displacement, and W is 'wedged' into the minor groove. In the present study, we conducted 19 F NMR, CD, Tm, and modeling experiments at various primer positions with respect to a template modified by a fluorine tagged AF-adduct (FAF). In the first set, the FAF-G was paired with C and in the second set it was paired with A. The FAF-G:C oligonucleotides were found to preferentially adopt the B-or S-conformers while the FAF-G:A mismatch ones preferred the B-and W-conformers. The conformational preferences of both series were dependent on temperature and complementary strand length; the largest differences in conformation were displayed at lower temperatures. The CD and Tm results are in general agreement with the NMR data. Molecular modeling indicated that the aminofluorene moiety in the minor groove of the W-conformer would impose a steric clash with the tight-packing amino acid residues on the DNA binding area of the Bacillus fragment (BF), a replicative DNA polymerase. In the case of the B-type conformer, the carcinogenic moiety resides in the solvent-exposed major groove throughout the replication/ translocation process. The present dynamic NMR results, combined with previous primer extension kinetic data by Miller and Grollman, support a model in which adduct-induced conformational heterogeneities at positions remote from the replication fork affect polymerase function through a long-range DNA-protein interaction.

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Section: And N-(2′-deoxyguanosin-8-yl)-2-aminofluorene (Af)mentioning

confidence: 99%

“…However, many specific details of this paradigm remains unknown, i.e., how does the polymerase switch at a site of DNA damage really occur? (27) Mutagenic outcomes in replicative polymerases may also contribute to the overall mutagenic burden in vivo (30).…”

Section: And N-(2′-deoxyguanosin-8-yl)-2-aminofluorene (Af)mentioning

confidence: 99%

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Meneni¹,

Liang²,

Cho³

2007

Journal of Molecular Biology

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“…The dilemma is how polymerases "sense" which DNA base is in the active site and how the process selects the appropriate base prior to the phosphodiester bond formation step, which "seals" the choice unless exonuclease or repair processes intervene later. The details of this sensing, and the obligate conformational changes necessary to amplify the energy involved in recognition (16), are still controversial (17)(18)(19)(20). The situation can be much more mechanistically complex when a modified base is present in the DNA substrate (19).…”

mentioning

confidence: 99%

Structure-Function Relationships in Miscoding by Sulfolobus solfataricus DNA Polymerase Dpo4: GUANINE N2,N2-DIMETHYL SUBSTITUTION PRODUCES INACTIVE AND MISCODING POLYMERASE COMPLEXES

Zhang

Eoff

Kozekov

et al. 2009

Journal of Biological Chemistry

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“…Likewise, X-ray crystallographic structures of Dpo4 in complex with DNA, both with and without dNTP have been determined (for example, see Refs [4,[13][14][15][16][17]). Crystal structures of lesion-containing complexes for these two polymerases are also available (for example, see Refs [14,[18][19][20][21][22][23][24][25][26][27]), which shed light on their contrasting mechanisms for processing damaged DNA templates.…”

mentioning

confidence: 99%

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

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

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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

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Interactions of Carcinogen-Bound DNA with Individual DNA Polymerases

Cited by 101 publications

References 267 publications

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Structure-Function Relationships in Miscoding by Sulfolobus solfataricus DNA Polymerase Dpo4: GUANINE N2,N2-DIMETHYL SUBSTITUTION PRODUCES INACTIVE AND MISCODING POLYMERASE COMPLEXES

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

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