Differential Impact of Mouse<i>Rad9</i>Deletion on Ionizing Radiation-Induced Bystander Effects

Zhu, Aiping; Zhou, Hongning; Leloup, Corinne; Marino, Stephen; Geard, Charles R.; Hei, Tom K.; Lieberman, Howard B.

doi:10.1667/rr3458.1

Cited by 23 publications

(22 citation statements)

References 28 publications

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“…The percentage of Mrad9 −/− apoptotic cells (10.58%) was higher than that of Mrad9 +/− cells (Fig 4D). The inhibitory effect of Rad9 on apoptosis was consistent with previously reported effects on murine embryonic stem cells (35) and chicken ET40 cells (36). …”

Section: Resultssupporting

confidence: 91%

Targeted Deletion of Rad9 in Mouse Skin Keratinocytes Enhances Genotoxin-Induced Tumor Development

Liu

Zhang

et al. 2008

Cancer Research

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The Rad9 gene is evolutionarily conserved from yeast to human, and plays crucial roles in genomic maintenance, DNA repair and cell cycle checkpoint controls. However, the function of this gene with respect to tumorigenesis is not well understood. A Rad9-null mutation in mice causes embryonic lethality. In this study, we created mice in which mouse Rad9, Mrad9, was deleted only in keratinocytes to permit examination of the potential function of the gene in tumor development. Mice with Mrad9+/− or Mrad9−/− keratinocytes demonstrated no overt, spontaneous morphological defects and appeared similar to wild-type controls. Painting the carcinogen 7,12-dimethylbenzanthracene (DMBA) onto the skin of the animals caused earlier onset and more frequent formation of tumors and senile skin plaques in Mrad9−/− mice, compared to Mrad9+/− and Mrad9+/+ littermates. DNA damage response genes p21, p53 and Mrad9B were expressed at higher levels in Mrad9−/− relative to Mrad9+/+ skin. Keratinocytes isolated from Mrad9−/− skin had more spontaneous and DMBA-induced DNA double strand breaks than Mrad9+/+ keratinocytes, and the levels were reduced by incubation with the antioxidant EGCG. These data suggest that Mrad9 plays an important role in maintaining genomic stability and preventing tumor development in keratinocytes.

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Section: Resultssupporting

confidence: 91%

Targeted Deletion of Rad9 in Mouse Skin Keratinocytes Enhances Genotoxin-Induced Tumor Development

Liu

Zhang

et al. 2008

Cancer Research

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“…The newly designed strip mylar dishes were used in the present studies as described (14,22). Exponentially growing U o and U + cells were plated in the concentric strip mylar dishes a couple of days before irradiation to ensure a confluent state.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects

Zhou¹,

Ivanov²,

Lien³

et al. 2008

Cancer Research

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Although radiation-induced bystander effects have been well described over the past decade, the mechanisms of the signaling processes involved in the bystander phenomenon remain unclear. In the present study, using the Columbia University charged particle microbeam, we found that mitochondrial DNA-depleted human skin fibroblasts (R o ) showed a higher bystander mutagenic response in confluent monolayers when a fraction of the same population were irradiated with lethal doses compared with their parental mitochondrial-functional cells (R + ). However, using mixed cultures of R o and R + cells and targeting only one population of cells with a lethal dose of A-particles, a decreased bystander mutagenesis was uniformly found in nonirradiated bystander cells of both cell types, indicating that signals from one cell type can modulate expression of bystander response in another cell type. In addition, we found that Bay 11-7082, a pharmacologic inhibitor of nuclear factor-KB (NF-KB) activation, and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a scavenger of nitric oxide (NO), significantly decreased the mutation frequency in both bystander R o and R + cells. Furthermore, we found that NF-KB activity and its dependent proteins, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), were lower in bystander R o cells when compared with their R + counterparts. Our results indicated that mitochondria play an important role in the regulation of radiation-induced bystander effects and that mitochondriadependent NF-KB/iNOS/NO and NF-KB/COX-2/prostaglandin E2 signaling pathways are important to the process. [Cancer Res 2008;68(7):2233-40]

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“…It is well established in cell lines that RAD9A has an antiapoptotic function (Kobayashi et al, 2004), and Rad9a 2/2 mouse ES cells demonstrate high spontaneous levels of apoptosis (Zhu et al, 2005). We therefore assessed the number of apoptotic cells by TUNEL staining in histological testicular sections obtained from the infertile mice used in the fertility study ( Fig.…”

Section: Rad9a-deficient Germ Cells Are Eliminated By Apoptosismentioning

confidence: 99%

The DNA damage checkpoint protein RAD9A is essential for male meiosis in the mouse

Vasil’eva

Hopkins

Wang

et al. 2013

Journal of Cell Science

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SummaryIn mitotic cells, RAD9A functions in repairing DNA double-strand breaks (DSBs) by homologous recombination and facilitates the process by cell cycle checkpoint control in response to DNA damage. DSBs occur naturally in the germline during meiosis but whether RAD9A participates in repairing such breaks is not known. In this study, we determined that RAD9A is indeed expressed in the male germ line with a peak of expression in late pachytene and diplotene stages, and the protein was found associated with the XY body. As complete loss of RAD9A is embryonic lethal, we constructed and characterized a mouse strain with Stra8-Cre driven germ cell-specific ablation of Rad9a beginning in undifferentiated spermatogonia in order to assess its role in spermatogenesis. Adult mutant male mice were infertile or sub-fertile due to massive loss of spermatogenic cells. The onset of this loss occurs during meiotic prophase, and there was an increase in the numbers of apoptotic spermatocytes as determined by TUNEL. Spermatocytes lacking RAD9A usually arrested in meiotic prophase, specifically in pachytene. The incidence of unrepaired DNA breaks increased, as detected by accumulation of cH2AX and DMC1 foci on the axes of autosomal chromosomes in pachytene spermatocytes. The DNA topoisomerase IIb-binding protein 1 (TOPBP1) was still localized to the sex body, albeit with lower intensity, suggesting that RAD9A may be dispensable for sex body formation. We therefore show for the first time that RAD9A is essential for male fertility and for repair of DNA DSBs during meiotic prophase I.

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Differential Impact of MouseRad9Deletion on Ionizing Radiation-Induced Bystander Effects

Cited by 23 publications

References 28 publications

Targeted Deletion of Rad9 in Mouse Skin Keratinocytes Enhances Genotoxin-Induced Tumor Development

Targeted Deletion of Rad9 in Mouse Skin Keratinocytes Enhances Genotoxin-Induced Tumor Development

Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects

The DNA damage checkpoint protein RAD9A is essential for male meiosis in the mouse

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