A role for DNA polymerase V in G→T mutations from the major benzo[a]pyrene N2-dG adduct when studied in a 5′-TT sequence in E. coli

Yin, Jun; Seo, Kwang Young; Loechler, Edward L.

doi:10.1016/j.dnarep.2003.11.012

Cited by 29 publications

(34 citation statements)

References 136 publications

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“…However, induction of the SOS response in E. coli increases bypass of bulky adducts, including (ϩ)-ta[BP]G, with a significant increase in both error-free and error-prone events (49,51,60,66); this suggests that Y-family DNA polymerases, including pol IV and pol V, evolved to overcome replication hurdles in order to increase cellular survival (6,60). In agreement, a recent study suggests two mutagenic pathways for G 3 T mutations in E. coli dictated by sequence context, one of which is dependent on DNA polymerase V, a Y-family DNA polymerase (67). Indeed, bulky adducts, such as (ϩ)-ta[BP]G, predominantly block replicative DNA polymerases (47, 56 -58, 68 -70), but members of the Y-family, including pol (71), pol (64), and pol (63), bypass these adducts more readily than their replicative counterparts, albeit with reduced efficiency when compared with that in undamaged DNA (4,7,20,63,71).…”

supporting

confidence: 68%

The Spacious Active Site of a Y-Family DNA Polymerase Facilitates Promiscuous Nucleotide Incorporation Opposite a Bulky Carcinogen-DNA Adduct

Perlow-Poehnelt

Likhterov

Scicchitano

et al. 2004

Journal of Biological Chemistry

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supporting

confidence: 68%

The Spacious Active Site of a Y-Family DNA Polymerase Facilitates Promiscuous Nucleotide Incorporation Opposite a Bulky Carcinogen-DNA Adduct

Perlow-Poehnelt

Likhterov

Scicchitano

et al. 2004

Journal of Biological Chemistry

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“…1C). This mechanism clearly supports a link between base substitutions and frameshift mutations and suggests a straightforward explanation for 5Ј sequence dependence in base substitutions induced by the bulky adducts in E. coli (2,12,30,32).…”

Section: Bp-dg Looping-out and ؊1 Frameshift Mutationsmentioning

confidence: 79%

“…In consequence, the base 5Ј determines the identity of the base incorporated opposite the lesion, which is referred as the 5Ј rule (20). The mutations induced by BP-dG in Escherichia coli are Ͼ95% G 3 T in a 5Ј-TG*C sequence and Ͼ95% G 3 A in a 5Ј-AG*A sequence, respectively, which follow the 5Ј rule and are Y-family polymerase-dependent (12,29,30). The 5Ј rule is also clearly demonstrated by the present replication assays on templates that have four different bases 5Ј to the BP-dG lesion (Fig.…”

Section: Bp-dg Looping-out and ؊1 Frameshift Mutationsmentioning

confidence: 99%

“…The loop-out of BP-dG provides a structural basis for 5Ј sequence-dependent base substitutions and Ϫ1 frameshift mutations induced by the major BP-dG adduct in vivo (11,12,29,30). Once the lesion is looped out by template misalignment, primer extension proceeds by using the nucleotide 5Ј to the lesion as template for incoming nucleotides.…”

Section: Bp-dg Looping-out and ؊1 Frameshift Mutationsmentioning

confidence: 99%

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A structural gap in Dpo4 supports mutagenic bypass of a major benzo[ a ]pyrene dG adduct in DNA through template misalignment

Bauer

Xing²,

Yagi³

et al. 2007

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

139

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Erroneous replication of lesions in DNA by DNA polymerases leads to elevated mutagenesis. To understand the molecular basis of DNA damage-induced mutagenesis, we have determined the x-ray structures of the Y-family polymerase, Dpo4, in complex with a DNA substrate containing a bulky DNA lesion and incoming nucleotides. The DNA lesion is derived from an environmentally widespread carcinogenic polycyclic aromatic hydrocarbon, benzo[ a ]pyrene (BP). The potent carcinogen BP is metabolized to diol epoxides that form covalent adducts with cellular DNA. In the present study, the major BP diol epoxide adduct in DNA, BP- N 2 -deoxyguanosine (BP–dG), was placed at a template–primer junction. Three ternary complexes reveal replication blockage, extension past a mismatched lesion, and a −1 frameshift mutation. In the productive structures, the bulky adduct is flipped/looped out of the DNA helix into a structural gap between the little finger and core domains. Sequestering of the hydrophobic BP adduct in this new substrate-binding site permits the DNA to exhibit normal geometry for primer extension. Extrusion of the lesion by template misalignment allows the base 5′ to the adduct to serve as the template, resulting in a −1 frameshift. Subsequent strand realignment produces a mismatched base opposite the lesion. These structural observations, in combination with replication and mutagenesis data, suggest a model in which the additional substrate-binding site stabilizes the extrahelical nucleotide for lesion bypass and generation of base substitutions and −1 frameshift mutations.

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“…These lesions can produce mutations on replication in vitro and in vivo [74][75][76]. Such mutations, when present in DNA sequences that regulate the cell cycle, can trigger cancer initiation [72].…”

Section: Box 3 Benzo[a]pyrene-derived Dna Lesionsmentioning

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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A role for DNA polymerase V in G→T mutations from the major benzo[a]pyrene N2-dG adduct when studied in a 5′-TT sequence in E. coli

Cited by 29 publications

References 136 publications

The Spacious Active Site of a Y-Family DNA Polymerase Facilitates Promiscuous Nucleotide Incorporation Opposite a Bulky Carcinogen-DNA Adduct

The Spacious Active Site of a Y-Family DNA Polymerase Facilitates Promiscuous Nucleotide Incorporation Opposite a Bulky Carcinogen-DNA Adduct

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[ a ]pyrene dG adduct in DNA through template misalignment

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

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