Parp-1 deficiency causes an increase of deletion mutations and insertions/rearrangements in vivo after treatment with an alkylating agent

Shibata, Atsushi; Kamada, Nobuo; Masumura, Ken-ichi; Nohmi, Takehiko; Kobayashi, Shizuko; Teraoka, Hirobumi; Nakagama, Hitoshi; Sügimura, Takashi; Suzuki, Hiroshi; Masutani, Mitsuko

doi:10.1038/sj.onc.1208289

Cited by 61 publications

(43 citation statements)

References 56 publications

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“…No significant differences in spontaneous MFs were reported in p53, Atm or Parp-1 knockout gpt delta mice, although heavy-ion or X-ray irradiation induced more large deletions in knockout mice than in wild type mice. 17,21,26) In the gpt delta rat, the spontaneous Spi − MFs we have obtained from 13 rat tissues were between 1.3 × 10 −6 and 4.4 × 10 −6 , similar to those observed in gpt delta mice. 12) No marked strain difference has been observed between SD and F344 rats although additional studies are needed to confirm this finding.…”

Section: Spi − Assay (Spi − Selection) For Deletionssupporting

confidence: 48%

“…The gpt and Spi − assay systems have been validated primarily in mice with many chemical mutagens/carcinogens, UV and ionizing radiation, for which mutagenicity, organ specificity and mutation spectrum have been thoroughly characterized. 1,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Recently, the outbred gpt delta SD rat was backcrossed with Fisher 344 (F344) rat, to establish an inbred gpt delta rat (F344). In this review, we focus on the spontaneous mutations detected by the gpt and Spi − assays in gpt delta mice and rats and discuss possible mechanisms underlying these in vivo mutations.…”

Section: Overview Of Gpt Delta Transgenic Rodentsmentioning

confidence: 99%

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Spontaneous Mutagenesis in Rodents: Spontaneous Gene Mutations Identified by Neutral Reporter Genes in gpt Delta Transgenic Mice and Rats

Masumura

Nohmi

2009

JOURNAL OF HEALTH SCIENCE

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Transgenic rodents are valuable models for investigation of genotoxicity of chemicals in vivo. We have developed gpt delta transgenic mice (C57BL/6J background) and rats (Sprague-Dawley, SD), which have the ability to identify both point mutations by the gpt assay [6-thioguanine (6-TG) selection] and certain types of deletions by the Spi − (Spi, sensitive to P2 interference) assay. Recently, the gpt delta SD rat was backcrossed with the Fisher 344 (F344) rat to establish an gpt delta F344 rat. The average spontaneous gpt mutation frequencies (MFs) are about 4.5 × 10 −6 in both SD and F344 gpt delta rats as well as in gpt delta mice. The G:C to A:T transitions at 5 -CpG-3 sites and G:C to T:A transversions are the predominant spontaneous gpt mutations in rats and mice. However, there is one false mutation (e.g. A:T to T:A at position 299) in the rats. The base substitution may have arisen when the lambda EG10 transgene was introduced into the genome of the SD rat during transgenesis. In the Spi − assay, 1-bp deletions in repetitive sequences are predominantly observed in both mice and rats. Possible mechanisms underlying the spontaneous mutations in gpt delta rodents are discussed.Key words --gpt delta transgenic rodent, spontaneous mutation, mutation spectrum, gpt assay, Spi − assay OVERVIEW OF gpt DELTA TRANSGENIC RODENTSGene mutations play an important role in the etiology of many human diseases including cancer. Since humans are exposed to a variety of endogenous and exogenous mutagens, there has been considerable interest in the relationship between exposure, genotoxic effects, and cancer incidence. To assess the risk of mutagens to the human genome, genotoxicity tests have been developed, including in vivo mutation assays using experimental animals, which play a crucial role in risk assessment. To investigate in vivo genotoxicity, a number of transgenic rodent mutation assays have been developed by introducing reporter transgenes into the chromosome of every cell of the animal. 1, 2) Using these systems, mutagenic events induced in a rodent can * To whom correspondence should be addressed: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. Tel.: +81-3-3700-1141 (Ext. 280); Fax: +81-3-3707-6950; E-mail: masumura@nihs.go.jp be detected by recovering the transgene and analyzing the phenotype of the reporter gene in a bacterial host. These models permit quantitation of mutations and identification at the sequence level in any tissue or organ in the body. lacZ, lacI or cII have been employed as reporter genes in transgenic rodents, such as the Muta TM mouse, and the Big Blue R mouse and rat. 3-7) Despite differences in size and sequence context, spontaneous mutation frequencies of these reporter genes are in the mid-10 −5 range and those are predominantly base substitutions in most tissues. This high background of base substitutions may make it difficult to detect rare mutations such as deletions induced by ionizing radiation. 8,9) To...

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Section: Spi − Assay (Spi − Selection) For Deletionssupporting

confidence: 48%

Section: Overview Of Gpt Delta Transgenic Rodentsmentioning

confidence: 99%

Spontaneous Mutagenesis in Rodents: Spontaneous Gene Mutations Identified by Neutral Reporter Genes in gpt Delta Transgenic Mice and Rats

Masumura

Nohmi

2009

JOURNAL OF HEALTH SCIENCE

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“…Recent studies using PARP-1 mutant mice have implicated PARP-1 in the suppression of tumorigenesis (Tong et al, 2001a;Masutani et al, 2003). Although PARP-1À/À mice develop spontaneous tumors at a low incidence (Tong et al, 2002), they are susceptible to chemical carcinogeninduced tumorigenesis, with increased mutation rates (Tsutsumi et al, 2001;Nozaki et al, 2003;Shibata et al, 2005). Inactivation of PARP-1 has been shown to result in a high frequency of T-cell lymphomas in severe combined immunodeficiency mice (Morrison et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice

et al. 2006

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The DNA strand break-binding molecule, poly(ADPribose) polymerase-1 (PARP-1), plays a role in DNA repair, chromosomal stability, transcription and cell death. Accumulating evidence suggests that dysfunction of PARP-1 contributes to tumorigenesis. Here, we report that PARP-1 deficiency causes mammary carcinoma formation in female mice, and that the introduction of Trp53 mutations accelerates the onset and shortens the latency of mammary tumorigenesis. We show that PARP-1 deficiency results in chromosomal aneuploidy and centrosome amplification, which are substantiated by the inactivation of Trp53 in primary mammary epithelial (PME) cells. In addition, PARP-1 deficiency compromises p53 activation and impairs BRCA1 recruitment to the sites of DNA damage in PME cells. PARP-1 complementation partly rescues the defective DNA damage response mediated by p53 and BRCA1. The present study thus identifies a role of PARP-1 in suppressing mammary tumorigenesis in vivo and suggests that dysfunction of PARP-1 may be a risk factor for breast cancer in humans.

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“…In support of this hypothesis, it has recently been reported that the genomes of PARP-1 null mice show an increased incidence of deletion mutations upon DNA damage (Shibata et al, 2005).…”

Section: Poly(adp-ribose)polymerasementioning

confidence: 56%

Targeting base excision repair to improve cancer therapies

Sharma

Dianov

2007

Molecular Aspects of Medicine

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Most commonly used cancer therapies, particularly ionizing radiation and certain classes of cytotoxic chemotherapies, cause cell death by damaging DNA. Base excision repair (BER) is the major system responsible for the removal of corrupt DNA bases and repair of DNA single strand breaks generated spontaneously and induced by exogenous DNA damaging factors such as certain cancer therapies. In this review, the physico-chemical properties of the proteins involved in BER are discussed with particular emphasis on molecular mechanisms coordinating repair processes. The aim of this review is to apply extensive knowledge that currently exists regarding the biochemical mechanisms involved in human BER to the molecular biology of current therapies for cancer. It is anticipated that the application of this knowledge will translate into the development of novel effective therapies for improving existing treatments such as radiation therapy and oxaliplatin chemotherapy.2

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Parp-1 deficiency causes an increase of deletion mutations and insertions/rearrangements in vivo after treatment with an alkylating agent

Cited by 61 publications

References 56 publications

Spontaneous Mutagenesis in Rodents: Spontaneous Gene Mutations Identified by Neutral Reporter Genes in gpt Delta Transgenic Mice and Rats

Spontaneous Mutagenesis in Rodents: Spontaneous Gene Mutations Identified by Neutral Reporter Genes in gpt Delta Transgenic Mice and Rats

Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice

Targeting base excision repair to improve cancer therapies

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