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Journal Articles

Significance of DNA Polymerase I in ${it in vivo}$ processing of clustered DNA damage

Shikazono, Naoya; Akamatsu, Ken; Takahashi, Momoko*; Noguchi, Miho; Urushibara, Ayumi; O'Neill, P.*; Yokoya, Akinari

Mutation Research; Fundamental and Molecular Mechanisms of Mutagenesis, 749(1-2), p.9 - 15, 2013/09

 Times Cited Count:11 Percentile:40.54(Biotechnology & Applied Microbiology)

We examined the biological consequences of bi-stranded clustered damage sites, consisting of a combination of DNA lesions using a bacterial plasmid-based assay. The transformation efficiencies were significantly lower for the bi-stranded clustered GAP/AP lesions than for either a single GAP or a single AP site. When the two lesions were separated by 10-20 bp, the transformation efficiencies were comparable with those of the single lesions. This recovery of transformation efficiency for separated lesions requires DNA polymerase I (Pol I) activity. Analogously, the mutation frequency was enhanced in a bi-stranded cluster containing a GAP and an 8-oxoG, and Pol I was found to play an important role in minimising mutations induced as a result of clustered lesions. These results indicate that the biological consequences of clustered DNA damage strongly depend on Pol I activity.

Journal Articles

The Mutagenic potential of 8-oxoG/single strand break-containing clusters depends on their relative positions

Noguchi, Miho; Urushibara, Ayumi; Yokoya, Akinari; O'Neill, P.*; Shikazono, Naoya

Mutation Research; Fundamental and Molecular Mechanisms of Mutagenesis, 732(1-2), p.34 - 42, 2012/04

 Times Cited Count:14 Percentile:44.02(Biotechnology & Applied Microbiology)

The effect of a single strand break associated with base lesion(s) in vivo remains largely unknown. In the present study we determined the mutagenicities of two- and three-lesion clustered damage sites containing a 1-nucleotide gap (GAP) and 8-oxo-7,8-dihydroguanine(s) (8-oxoG(s)). The mutation frequencies (MFs) of bi-stranded two-lesion clusters (GAP/8-oxoG), especially in mutY-deficient strains, were high and were similar to those for bi-stranded clusters with 8-oxoG and base lesions/AP sites, suggesting that the GAP is processed with an efficiency similar to the efficiency of processing a base lesion or an AP site within a cluster. The MFs of tandem two-lesion clusters comprised of a GAP and an 8-oxoG were comparable to or less than the MF of a single 8-oxoG. The mutagenic potential of three-lesion clusters, which were comprised of a tandem lesion (a GAP and an 8-oxoG) and an opposing single 8-oxoG, was higher than that of a single 8-oxoG, but was no more than that of a bi-stranded 8-oxoGs. We suggest that incorporation of a nucleotide opposite 8-oxoG is less mutagenic when a GAP is present in a cluster than when a GAP is absent. Our observations indicate that the repair of a GAP is retarded by an opposing 8-oxoG, but not by a tandem 8-oxoG, and that the extent of GAP repair determines the biological consequences.

Journal Articles

Biological consequences of potential repair intermediates of clustered base damage site in Escherichia coli

Shikazono, Naoya; O'Neill, P.*

Mutation Research; Fundamental and Molecular Mechanisms of Mutagenesis, 669(1-2), p.162 - 168, 2009/11

 Times Cited Count:17 Percentile:48.3(Biotechnology & Applied Microbiology)

Journal Articles

Induction of DNA strand breaks, base lesions and clustered damage sites in hydrated plasmid DNA films by ultrasoft X rays around the phosphorus K edge

Yokoya, Akinari; Cunniffe, S. M. T.*; Watanabe, Ritsuko; Kobayashi, Katsumi*; O'Neill, P.*

Radiation Research, 172(3), p.296 - 305, 2009/09

 Times Cited Count:25 Percentile:63.7(Biology)

To characterize the DNA damage induced by K-shell ionization of phosphorus atom in DNA backbone on the level of hydration, the yields of DNA strand breaks and base lesions arising from the interaction of ultrasoft X-rays (USX) with energies around the phosphorus K-edge were determined using dry and fully hydrated pUC18 plasmid DNA samples. Base lesions and bistranded clustered DNA damage sites were revealed by post-irradiation treatment with the base excision repair proteins, Nth and Fpg. The complex types of damage, prompt and enzymatically induced DSB are preferentially induced by phosphorus K-resonance at 2153 eV rather than simple SSB and isolated base lesions particularly in hydrated conditions. It is concluded that not only the phosphorus K-resonance and resulting emission of low energy LMM-Auger electrons ($$sim$$120 eV) but also the level of hydration plays an important role in the induction of complex damage in plasmid DNA.

Journal Articles

Processing of thymine glycol in a clustered DNA damage site; Mutagenic or cytotoxic

Bellon, S.*; Shikazono, Naoya; Cunniffe, S. M. T.*; Lomax, M.*; O'Neill, P.*

Nucleic Acids Research, 37(13), p.4430 - 4440, 2009/07

 Times Cited Count:43 Percentile:70.5(Biochemistry & Molecular Biology)

Journal Articles

LET dependence of the yield of single-, double-strand breaks and base lesions in fully hydrated plasmid DNA films by $$^{4}$$He$$^{2+}$$ ion irradiation

Urushibara, Ayumi*; Shikazono, Naoya; O'Neill, P.*; Fujii, Kentaro; Wada, Seiichi*; Yokoya, Akinari

International Journal of Radiation Biology, 84(1), p.23 - 33, 2008/01

 Times Cited Count:33 Percentile:90.3(Biology)

To characterize the complexity of radiation damage to DNA, fully hydrated plasmid DNA was irradiated with $$^{4}$$He$$^{2+}$$ ions. From quantification of the conformational changes of the irradiated samples, the yields of single-(SSB) and double strand break (DSB) were obtained. Base lesions were visualized as additional strand breaks by treatment with base excision repair enzymes. The yield of prompt SSBs does not depend significantly on LET of the $$^{4}$$He$$^{2+}$$ ions, whereas the yield of prompt DSBs increases with increasing LET. The yields of isolated base lesions, revealed by enzymes as additional SSBs, decrease drastically with increasing LET. The sum of the yields of DSB and additional DSBs revealed by the enzymes increase with increasing LET of the $$^{4}$$He$$^{2+}$$ ions except at the highest LET investigated. These results indicate that the yields of clustered damage, revealed as DSB and non-DSB clustered damage sites, increase with increasing ionization density of radiation.

Journal Articles

DNA damage induced by the direct effect of He ion particles

Urushibara, Ayumi; Shikazono, Naoya; Watanabe, Ritsuko; Fujii, Kentaro; O'Neill, P.*; Yokoya, Akinari

Radiation Protection Dosimetry, 122(1-4), p.163 - 165, 2006/12

 Times Cited Count:3 Percentile:25.6(Environmental Sciences)

no abstracts in English

Journal Articles

The Roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage

Shikazono, Naoya; Pearson, C.*; O'Neill, P.*; Thacker, J.*

Nucleic Acids Research, 34(13), p.3722 - 3730, 2006/08

 Times Cited Count:54 Percentile:71.74(Biochemistry & Molecular Biology)

no abstracts in English

Journal Articles

Molecular dynamics simulation of clustered DNA damage sites containing 8-oxoguanine and abasic site

Fujimoto, Hirofumi*; Pinak, M.; Nemoto, Toshiyuki*; O'Neill, P.*; Kume, Etsuo; Saito, Kimiaki; Maekawa, Hideaki*

Journal of Computational Chemistry, 26(8), p.788 - 798, 2005/06

 Times Cited Count:23 Percentile:59.12(Chemistry, Multidisciplinary)

Clustered DNA damage sites induced by ionizing radiation have been suggested to have serious consequences to organisms. In this study, approaches based on molecular dynamics (MD) simulation have been applied to examine conformational changes and energetic properties of DNA molecules containing clustered damage sites consisting of 2 lesioned sites, 8-oxoG and AP site. After 1 nanosecond of MD simulation, one of the 6 DNA molecules containing a clustered damage site develop specific characteristic features: sharp bending at the lesioned site and weakening or complete loss of electrostatic interaction energy between 8-oxoG and bases locating on the complementary strand. From these results it is suggested that these changes would make it difficult for the repair enzyme to bind to the lesions within the clustered damage site and thereby result in a reduction of its repair capacity.

Journal Articles

Molecular dynamics of 8-oxoguanine lesioned B-DNA molecule; Structure and energy analysis

Pinak, M.; O'Neill, P.*; Fujimoto, Hirofumi; Nemoto, Toshiyuki*

AIP Conference Proceedings 708, p.310 - 313, 2004/05

The multiple nanosecond molecular dynamics simulations of DNA mutagenic oxidative lesion - 7,8-dihydro-8-oxoguanine (8-oxoG), complexed with the repair enzyme - human oxoguanine glycosylase 1 (hOGG1) in a physiological aqueous environment, were performed in order to describe the structural and energy changes in DNA and the dynamical process of DNA-enzyme complex formation. In complex the N-terminus of arginine 324 was found located close to the phosphodiester bond of the nucleotide with 8-oxoG enabling chemical reaction(s) between the amino acid and the lesion. The recognition of lesion on DNA, its recognition by repair enzyme and the formation of stable DNA-enzyme complex are necessary conditions for the onset of the successful enzymatic repair process.

Journal Articles

Effects of hydration on the induction of strand breaks, base lesions, and clustered damage in DNA films by $$alpha$$-radiation

Yokoya, Akinari; Cunniffe, S. M. T.*; Stevens, D. L.*; O'Neill, P.*

Journal of Physical Chemistry B, 107(3), p.832 - 837, 2003/01

 Times Cited Count:25 Percentile:57.3(Chemistry, Physical)

no abstracts in English

Journal Articles

Effect of hydration on the induction of strand breaks and base lesions in plasmid DNA films by $$gamma$$-radiation

Yokoya, Akinari; Cunniffe, S. M. T.*; O'Neill, P.*

Journal of the American Chemical Society, 124(30), p.8859 - 8866, 2002/07

 Times Cited Count:84 Percentile:87.91(Chemistry, Multidisciplinary)

no abstracts in English

Oral presentation

Mutagenic potential of clustered DNA damage site in ${it Escherichia coli}$

Shikazono, Naoya; Pearson, C.*; Thacker, J.*; O'Neill, P.*

no journal, , 

no abstracts in English

Oral presentation

Mutagenic potential of clustered DNA damage site in ${it Escherichia coli}$

Shikazono, Naoya; Pearson, C.*; Thacker, J.*; O'Neill, P.*

no journal, , 

Clustered DNA damage induced by a single radiation track is a unique feature of ionizing radiation. Recent ${it in vitro}$ studies have shown that the repair of lesions within clusters may be retarded, but less is known about the processing and the mutagenic effects of such clustered damage in vivo. Using a bacterial plasmid-based assay, we have investigated the mutagenic potential of bistranded clustered damage sites which consist of 8-oxo-7,8-dihydroguanine (8-oxoG) and dihydrothymine (DHT) at defined separations. We found a significantly higher mutation frequency for the clustered DHT + 8-oxoG lesions than that for either a single 8-oxoG or a single DHT in wild-type and in glycosylase-deficient strains of ${it E. coli}$. From these results and similarities with the mutability of respective 8-oxoG + AP clusters, it is suggested that removal of 8-oxoG within clustered damage site is retarded, probably reflecting the preferential excision of DHT initially. For a certain fraction of clusters, 8-oxoG may be initially removed from the cluster. To gain further insights on the processing of the DHT + 8-oxoG cluster, several potential intermediates after 8-oxoG removal were assessed for their mutability. For instance, DHT + AP or DHT + Gap containing cluster, but not AP + AP or Gap +AP clusters, has a relatively low mutation frequency. Further, AP + AP or Gap + AP cluster had a reduced transformation efficiency. These results led us to suggest that, when either 8-oxoG or DHT is initially excised from a cluster containing 8-oxoG and DHT, the base remaining within the resulting damage will not be further converted to an AP site or to a single strand break ${it in vivo}$.

Oral presentation

Biological consequences of bistranded clustered DNA damage in ${it Escherichia coli}$

Shikazono, Naoya; Pearson, C.*; Thacker, J.*; O'Neill, P.*

no journal, , 

Clustered DNA damage induced by a single radiation track is a unique feature of ionizing radiation. Using a plasmid-based assay in ${it Escherichia coli}$, we found a significantly higher mutation frequency for the clustered DHT + 8-oxoG lesions than that for either a single 8-oxoG or a single DHT in wild-type and in glycosylase-deficient strains of ${it E. coli}$. To gain further insights on the processing of the DHT + 8-oxoG cluster, several potential intermediates after 8-oxoG removal were assessed. DHT + AP or DHT + Gap containing cluster had a relatively low mutation frequency, whereas AP + AP or Gap + AP cluster was found to strongly retard replication. These results led us to suggest that, when either 8-oxoG or DHT is initially excised from a cluster containing 8-oxoG and DHT, the remaining base damage will not be further converted to an AP site or to a single strand break ${it in vivo}$.

Oral presentation

Processing of clustered DNA damage sites which consist of 8-oxoG and DHT in ${it Escherichia coli}$

Shikazono, Naoya; Pearson, C.*; Thacker, J.*; O'Neill, P.*

no journal, , 

Clustered DNA damage induced by a single radiation track is a unique feature of ionizing radiation. Recent in vitro studies have shown that the repair of lesions within clusters may be retarded, but less is known about the processing and the mutagenic effects of such clustered damage in vivo. Using a plasmid-based assay in Escherichia coli, we have investigated the mutagenic potential of bistranded clustered damage sites which consist of 8-oxo-7,8-dihydroguanine (8-oxoG) and dihydrothymine (DHT) at defined separations. We found a significantly higher mutation frequency for the clustered DHT + 8-oxoG lesions than that for either a single 8-oxoG or a single DHT in wild-type and in glycosylase-deficient strains of ${it E. coli}$. Similar results were obtained with the 8-oxoG + AP cluster. To gain further insights on the processing of the DHT + 8-oxoG cluster, several potential intermediates were assessed. It was found that AP + AP and Gap + AP clusters strongly retard replication. These results led us to suggest that the base remaining within the cluster after removal of one of the base damage will not be further converted to an AP site or to a single strand break ${it in vivo}$.

Oral presentation

Mutagenic potential of 8-oxo-7,8-dihydroguanine depends on the location of a single strand break within a cluster

Noguchi, Miho; Urushibara, Ayumi*; Yokoya, Akinari; O'Neill, P.*; Shikazono, Naoya

no journal, , 

Ionizing radiation (IR) produces ionization and excitation along a radiation track, and generates, amongst other DNA lesions, clustered DNA damage sites in cellular DNA. Clustered DNA damage is defined as two or more lesions induced within 1-2 helical turns (10-20bp) of DNA. It has been reported that various types of SSB have a strong inhibitory effect on the excision of 8-oxo-7,8-dihydroguanine (8-oxoG) in vitro. In the present study, we used plasmid based assay in Escherichia coli to investigate the potential of SSB to influence the mutagenicity of 8-oxoG. As a model of clustered damage, we used synthesized oligonucleotides carrying an SSB and an 8-oxoG at a restriction enzyme recognition site. In single glycosylase-deficient strain mutY, the mutagenic potential of 8-oxoG was stimulated by an SSB situated on the opposite strand. This observation indicates that a SSB retards the incision of 8-oxoG by Fpg. On the other hand, when an SSB was placed in tandem with 8-oxoG on the same strand at varying separations, these tandem damage sites showed lower mutation frequency than a single 8-oxoG lesion in every strain. These results suggest that the 8-oxoG is removed, at least in part, during repair processing of the SSB. Our studies demonstrate that the mutagenic potential of 8-oxoG depends on whether the SSB is located on either the same strand or the opposite strand containing to 8-oxoG.

Oral presentation

Processing of clustered DNA damage site in ${it Escherichia coli}$

Shikazono, Naoya; Pearson, P.*; Thacker, J.*; O'Neill, P.*

no journal, , 

To gain insights on the processing of the DHT + 8-oxoG cluster in vivo, several potential intermediates after removal of base lesions were assessed for their transformation efficiency and mutability in the wild type strain of ${it Escherichia coli}$. DHT + AP or DHT + Gap containing cluster demonstrated relatively low mutation frequency. On the other hand, in the case of an AP + AP or Gap + AP cluster, in which a base damage is absent, transformation efficiencies were significantly reduced. From these results it is suggested that, when either 8-oxoG or DHT is initially excised from a cluster containing 8-oxoG and DHT, the modified base remaining within the resulting damage will not be converted into an AP site or to a single strand break in vivo.

Oral presentation

Biological consequences of clustered DNA damage containing a single strand break and an AP site

Shikazono, Naoya; Noguchi, Miho; Urushibara, Ayumi*; O'Neill, P.*; Yokoya, Akinari

no journal, , 

Using a bacterial plasmid-based assay, we have investigated the biological consequences of bistranded clustered damage sites which consist of a single strand break (SSB) and an apurinic/apyrimidinic (AP) site. We found a significantly lower transformation frequency for the cluster than that for either a single SSB or a single AP site, which implies that a double strand break is formed during the processing of the cluster. Also, when the two lesions were very close to each other, almost every plasmid possessed a mutation. The major types of mutation induced by the cluster were AP:C to C:G and a 1-bp deletion at the position of the AP:C pair. These results show a clear contrast to the results from clusters comprised of base lesions. We suggest that the biological consequences of clustered DNA damage strongly depends on the type of the comprising lesions.

Oral presentation

Mutagenic potential of clustered DNA damage containing single strand break and 8-oxoGs

Noguchi, Miho; Urushibara, Ayumi; Yokoya, Akinari; O'Neill, P.*; Shikazono, Naoya

no journal, , 

It is proposed that a single track of ionizing radiation induces clustered DNA damage sites and that their complexity increases with increasing LET. Non-DSB clustered damage is thought to contribute to the biological effects of radiation such as mutation. In this study, we have investigated the mutagenicity of clustered DNA damage containing SSB and base damage. We have used a plasmid based assay with Escherichia coli to measure the mutation frequency induced by bistranded clustered damage. As a model of clustered damage, we have synthesized oligonucleotides containing a SSB and/or 8-oxo-7,8-dihydroguanines (8-oxoGs) within the recognition site of the restriction enzyme (Alw26I). Plasmid constructs containing damaged DNA was transfected into wild-type or glycosylase-deficient strains and propagated in cells. The mutation frequency was assessed by the inability of Alw26I to cut the oligonucleotide sequence. The mutation frequency of bistranded clusters containing an 8-oxoG opposite to a second 8-oxoG 2bp apart was the highest of all the types of clusters tested in the present study. When a SSB was included in clusters containing bistranded 8-oxoGs, the mutation frequency is lower in all E. coli strains tested. These results suggest that a SSB located on the same strand to one of the 8-oxoG reduces the mutagenic potential of 8-oxoG. Our studies demonstrate that the mutagenic potential of clusters containing 8-oxoG is modified if a SSB is present within the cluster.

26 (Records 1-20 displayed on this page)