DNA Polymerase ^|^lambda; Promotes Mutagenesis Induced by 8-Oxo-7,8-dihydroguanine (8-hydroxyguanine) Paired with Adenine

Kamiya, Hiroyuki; Kurokawa, Masahiro

doi:10.3123/jemsge.2013.002

Cited by 3 publications

(3 citation statements)

References 38 publications

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“…The frequency of the A:T → C:G transversion induced by the G O :A pair was slightly but significantly decreased by WRN knockdown (Figure B). Similar reductions were observed when DNA pols η and λ were knocked down. , Since WRN interacts with these pols, the interactions might be related to the mutation pathway of the G O :A pair. − Additional studies from various viewpoints will be needed to reveal role(s) of WRN on this issue.…”

Section: Discussionmentioning

confidence: 81%

“…Similar reductions were observed when DNA pols η and λ were knocked down. 30,32 Since WRN interacts with these pols, the interactions might be related to the mutation pathway of the G O :A pair. 48−50 Additional studies from various viewpoints will be needed to reveal role(s) of WRN on this issue.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The formation of oxidatively damaged bases in nucleic acids is considered to cause mutagenesis, carcinogenesis, aging, and neurodegeneration. , 8-Oxo-7,8-dihydroguanine (G O , also known as 8-hydroxyguanine) is one of the major damaged nucleobases produced by ROS, and each day, 100–500 G O residues per cell are generated in DNA. − This oxidized G base exhibits ambiguous coding potential and has the ability to form base pairs with A as well as C. − G O is highly mutagenic and induces G:C → T:A and A:T → C:G transversion mutations when it is generated in the DNA and the nucleotide pool, respectively, in mammalian cells. − Many cellular proteins are involved in the mutagenesis pathway of the damaged base. Some BER and nucleotide pool sanitization enzymes prevent the mutations caused by G O , and some specialized DNA pols play protective and enhancive roles in the process. − …”

Section: Introductionmentioning

confidence: 99%

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Action-at-a-Distance Mutagenesis Induced by Oxidized Guanine in Werner Syndrome Protein-Reduced Human Cells

Kamiya

Yamazaki

Nakamura

et al. 2015

Chem. Res. Toxicol.

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8-Oxo-7,8-dihydroguanine (G(O), 8-hydroxyguanine) in DNA is one of the most important oxidatively damaged bases and causes G:C → T:A substitution mutations. The Werner syndrome protein (WRN) is a cancer-related RecQ DNA helicase and plays many roles in DNA replication and repair. To examine the relationships between G(O)-induced mutations and WRN, shuttle plasmid DNA containing a G(O):C pair in the supF gene was transfected into human U2OS cells, in which WRN was knocked down. The plasmid DNA replicated in the knockdown cells was introduced into an Escherichia coli indicator strain. The knockdown of WRN increased the mutant frequency of the G(O)-plasmid DNA. Unexpectedly, however, the WRN knockdown only slightly enhanced the targeted G:C → T:A mutation. Instead, base-substitution mutations at various positions were more frequently detected, with statistical significance. The results obtained in this study suggested that the reduction of the cancer-related WRN induced action-at-a-distance mutagenesis by the G(O):C pair in human cells. In addition, the WRN knockdown decreased the G(O):A-induced A:T → C:G mutations, suggesting that WRN may enhance the mutations caused by G(O) in the nucleotide pool.

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Section: Discussionmentioning

confidence: 81%

Section: ■ Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Action-at-a-Distance Mutagenesis Induced by Oxidized Guanine in Werner Syndrome Protein-Reduced Human Cells

Kamiya

Yamazaki

Nakamura

et al. 2015

Chem. Res. Toxicol.

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Mutations induced by 8-oxo-7,8-dihydroguanine in WRN- and DNA polymerase λ-double knockdown cells

et al. 2018

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Reactive oxygen species generate 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine), which induces G:C→T:A transversion mutations. The knockdowns of the protein responsible for Werner syndrome (WRN), a cancer-associated DNA helicase, and DNA polymerase (pol) λ, a WRN-interacting DNA pol, cause untargeted base-substitution mutations (action-at-a-distance mutations). To examine the consequences of the dual reductions of WRN and pol λ for the mutations caused by GO, siRNAs against both proteins were introduced into human U2OS cells. A replicable plasmid DNA with the oxidised nucleobase in a unique position of the supF gene was then introduced into the double knockdown cells. The amplified DNA recovered from the cells was used to transform a bacterial indicator strain. The mutant frequency and the subsequent sequence analysis revealed that the double knockdown additively promoted the G:C→T:A substitution at the GO position and increased the action-at-a-distance mutations to a level similar to that of the single WRN knockdown. Thus, WRN and DNA pol λ seem to suppress the targeted G:C→T:A mutation at least in part independently and reduce the untargeted mutations via an identical pathway.

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Induction of action-at-a-distance mutagenesis by 8-oxo-7,8-dihydroguanine in DNA pol λ-knockdown cells

et al. 2015

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IntroductionIn DNA, 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine) is one of the most pivotal oxidatively damaged bases and induces G:C → T:A transversion mutations. DNA polymerase λ preferentially inserts dCTP opposite GOin vitro, and this error-free bypass function is considered to be important after A base removal from GO:A pairs by the MUTYH DNA glycosylase. To examine the effects of reduced levels of DNA polymerase λ on the GO-induced mutations, the polymerase was knocked-down in human U2OS cells, and a shuttle plasmid DNA containing a GO:C pair at position 122 in the supF gene was transfected into the cells. The plasmid DNA replicated in the cells was introduced into an Escherichia coli indicator strain, to measure the supF mutant frequency.ResultsThe knockdown of DNA polymerase λ significantly enhanced the mutant frequency of the GO plasmid DNA. Contrary to our expectations, the knockdown did not promote the targeted G:C → T:A transversion. Instead, substitution mutations at G:C sites other than position 122 were enhanced in the cells.ConclusionsThese results suggested that the knockdown of DNA polymerase λ induced action-at-a-distance mutagenesis in human cells when the GO:C pair was present in the DNA.

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DNA Polymerase ^|^lambda; Promotes Mutagenesis Induced by 8-Oxo-7,8-dihydroguanine (8-hydroxyguanine) Paired with Adenine

Cited by 3 publications

References 38 publications

Action-at-a-Distance Mutagenesis Induced by Oxidized Guanine in Werner Syndrome Protein-Reduced Human Cells

Action-at-a-Distance Mutagenesis Induced by Oxidized Guanine in Werner Syndrome Protein-Reduced Human Cells

Mutations induced by 8-oxo-7,8-dihydroguanine in WRN- and DNA polymerase λ-double knockdown cells

Induction of action-at-a-distance mutagenesis by 8-oxo-7,8-dihydroguanine in DNA pol λ-knockdown cells

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