A Murine Model of Nijmegen Breakage Syndrome

Williams, Bret R.; Mirzoeva, Olga K.; Morgan, William F.; Lin, J. G.; Dunnick, Wesley A.; Petrini, John H.J.

doi:10.1016/s0960-9822(02)00763-7

Cited by 190 publications

(229 citation statements)

References 26 publications

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“…Likewise, the nibrin hypomorph Nbs1 DB/DB mouse showed an identical cellular phenotype after DNA damage to that of primary cultures derived from NBS patients including intra-S-phase checkpoint defects, chromosomal instability, and radiosensitivity (Williams et al, 2002). Additionally, the NBS1 m/m mouse model displayed lymphoma predisposition and infertility, as did the humanized mouse model hNbs1 657D5 (Kang et al, 2002;Difilippantonio et al, 2005).…”

Section: Modeling the Dna Dsb Response In The Mousementioning

confidence: 86%

“…The DNA-PK phenotype is less severe than that of the Ku-deficient mice, as they exhibit no growth defect or radiation sensitivity despite immunodeficiency (Taccioli et al, 1998;Gao et al, 1998a). Artemis and Microcephaly, ataxia, cerebellar development defects NBS1 À/À (Zhu et al, 2001) Embryonic lethality (BE7.5) NBS1 DB/DB (Williams et al, 2002) Cell cycle checkpoint defect in MEFs, synthetic lethal with Atm À/À HNbs1 657D5 (Difilippantonio et al, 2005) Impaired gonadal development, impaired lymphocyte development, lymphoma MRE11 Mre11 ATLD1/ATLD1 (Theunissen et al, 2003) Cell (Ludwig et al, 2001) Mammary tumors with median latency of 1.4 year MMTV-Cre; Brca2 F9À10 (Cheung et al, 2004) Mammary tumor with median latency of 1.6 year Nestin-Cre; Brca2 loxP/loxP (Frappart et al, 2007) Cerebellar development defect, impaired neurogenesis, p53 À/À rescues developmental defects and leads to medulloblastoma ATR Atr À/À (Brown and Baltimore, 2000) Embryonic lethality (before E7.5)…”

Section: Animal Models Of Nhej and Hr Deficienciesmentioning

confidence: 99%

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DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

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Section: Modeling the Dna Dsb Response In The Mousementioning

confidence: 86%

Section: Animal Models Of Nhej and Hr Deficienciesmentioning

confidence: 99%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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“…Two mice models of NBS have been developed, producing reduced amounts of a N-terminal truncated Nbs1 protein equivalent to the human p70 (Kang et al 2002, Williams et al 2002. These models recapitulated most of the cellular phenotypes of NBS patients.…”

Section: Animal Models For Mutations In the Mre11 Complexmentioning

confidence: 99%

The multiple roles of the Mre11 complex for meiotic recombination

2007

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During the first meiotic prophase, numerous DNA double-strand breaks (DSB) are formed in the genome in order to initiate recombination between homologous chromosomes. The conserved Mre11 complex, formed of Mre11, Rad50 and Nbs1 (Xrs2 in Saccharomyces cerevisiae) proteins, plays a crucial role in mitotic cells for sensing and repairing DSB. In meiosis the Mre11 complex is also required for meiotic recombination. Depending on the organisms, the Mre11 complex is required for the formation of the DSB catalysed by the transesterase Spo11 protein. It then plays a unique function in removing covalently attached Spo11 from the 5 ¶ extremity of the breaks through its nuclease activity, to allow further break resection. Finally, the Mre11 complex also plays a role during meiosis in bridging DNA molecules together and in sensing Spo11 DSB and activating the DNA damage checkpoint. In this article the different biochemical functions of the Mre11 complex required during meiosis are reviewed, as well as the consequences of Mre11 complex inactivation for meiosis in several organisms. Finally, I describe the meiotic phenotypes of several animal models that have been developed to model hypomorphic mutations of the Mre11 complex, involved in humans in some genetic instability disorders.

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“…Sensivity was determined by colony formation essentially as described (Williams et al 2002). Five thousand cells were treated for 2-3 h with etoposide (0-10 µg/mL), mitomycin C (0-3 µg/mL), or hydroxyurea (0-50 mM).…”

Section: Dna Damage Sensitivity Assaysmentioning

confidence: 99%

Cancer predisposition and hematopoietic failure in Rad50^S/S mice

Bender¹,

Sikes²,

Sullivan³

et al. 2002

Genes Dev.

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186

182

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Mre11, Rad50, and Nbs1 function in a protein complex that is central to the metabolism of chromosome breaks. Null mutants of each are inviable. We demonstrate here that hypomorphic Rad50 mutant mice (Rad50 S/S mice) exhibited growth defects and cancer predisposition. Rad50 S/S mice died with complete bone marrow depletion as a result of progressive hematopoietic stem cell failure. Similar attrition occurred in spermatogenic cells. In both contexts, attrition was substantially mitigated by p53 deficiency, whereas the tumor latency of p53 −/− and p53 +/− animals was reduced by Rad50 S/S . Indices of genotoxic stress and chromosomal rearrangements were evident in Rad50 S/S cultured cells, as well as in Rad50 S/S and p53 −/− Rad50 S/S lymphomas, suggesting that the Rad50 S/S phenotype was attributable to chromosomal instability. These outcomes were not associated with overt defects in the Mre11 complex's previously established double strand break repair and cell cycle checkpoint regulation functions. The data indicate that even subtle perturbation of Mre11 complex functions results in severe genotoxic stress, and that the complex is critically important for homeostasis of proliferative tissues.

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A Murine Model of Nijmegen Breakage Syndrome

Cited by 190 publications

References 26 publications

DNA double-strand break repair and development

DNA double-strand break repair and development

The multiple roles of the Mre11 complex for meiotic recombination

Cancer predisposition and hematopoietic failure in Rad50^S/S mice

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A Murine Model of Nijmegen Breakage Syndrome

Cited by 190 publications

References 26 publications

DNA double-strand break repair and development

DNA double-strand break repair and development

The multiple roles of the Mre11 complex for meiotic recombination

Cancer predisposition and hematopoietic failure in Rad50S/S mice

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Product

Resources

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Cancer predisposition and hematopoietic failure in Rad50^S/S mice