Radiation Induction of p53 in Cells from Nijmegen Breakage Syndrome Is Defective but Not Similar to Ataxia-Telangiectasia

Matsuura, K.; Balmukhanov, T. S.; Tauchi, Hiroshi; Weemaes, C.M.R.; Smeets, D.F.C.M.; Chrzanowska, Krystyna; Endou, S; Matsuura, Shinnya; Komatsu, Kenshi

doi:10.1006/bbrc.1997.7924

Cited by 44 publications

(23 citation statements)

References 19 publications

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“…These cells show defective S phase arrest, but an intermediate G1/S arrest. We have also observed impaired p53 stabilization and p21 induction in NBS and AT-5762ins137 cells (data not shown) consistent with results of others (Jongmans et al, 1997;Matsuura et al, 1998;Stewart et al, 2001). Based on these findings, we re-interpret results with NBS cells and argue that they are impaired in the response leading to G1/S arrest.…”

Section: H2ax Is Unique As Not Requiring Nbs1 Functionsupporting

confidence: 91%

“…AT-5762ins137 and NBS cells show similar radiosensitivity, slightly less than A-T null lines ( Figure 1a) and similar defective S phase arrest (RDS response), equivalent to that seen in A-T null cells (Figure 1b). The results for CZD82CH are similar to those obtained with other NBS cell lines (Girard et al, 2000;Matsuura et al, 1998;Stewart et al, 1999;Taalman et al, 1989). G1/S phase arrest was examined using a fluorescent activated cell sorting (FACS) technique and an intermediate dose-dependent defect in G1/S arrest is evident in AT-5762ins137 and CZD82CH cells, which contrasts with the pronounced defect in AT5BI ( Figure 1c).…”

Section: Examination Of Radiosensitivity and Cell Cycle Checkpoint Arsupporting

confidence: 80%

“…Based on our model that the different checkpoint assays respond differentially to low ATM activity, we argue that NBS cells are impaired in the G1/S response because: (a) the conclusion that NBS cells are proficient in G1/S arrest is based on results obtained following 5 -6 Gy, where efficient arrest is also seen in AT-5762ins137 cells; (b) the consensus published data show that NBS cells have impaired p53 stabilization and p21 induction similar to that observed in AT-5762ins137 (our unpublished results; Jongmans et al, 1997;Matsuura et al, 1998); (c) impaired G1/S arrest is seen in CZD82CH using 1 -3 Gy, the same conditions required to see a defect in AT-5762ins137 cells; and (d) a greater defect in S versus G1/S arrest does not necessitate an S phasespecific checkpoint response (it is seen in AT5762ins137 cells). Instead it can reflect the differential impact of reduced ATM activity.…”

Section: Discussionmentioning

confidence: 72%

“…At the cellular level, NBS cell lines show many of the phenotypic abnormalities displayed by A-T including chromosomal instability and radiation sensitivity (Featherstone and Jackson, 1998). However, whilst NBS cells display an RDS phenotype that is similar to that shown by A-T (Taalman et al, 1989), they show little, if any, impairment in G1/S or G2/M phase arrest (Antoccia et al, 1997(Antoccia et al, , 1999Jongmans et al, 1997;Matsuura et al, 1998;Stewart et al, 1999;Yamazaki et al, 1998) suggesting either that NBS1 is not required for these latter two checkpoints or that there is some level of redundancy. Additionally, radiation-induced activation of ATM kinase as well as the phosphoryla-tion of certain ATM dependent substrates (e.g.…”

Section: Introductionmentioning

confidence: 94%

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Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest

et al. 2002

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Cell lines from Nijmegen Breakage Syndrome (NBS) and ataxia telangiectasia (A-T) patients show defective S phase checkpoint arrest. In contrast, only A-T but not NBS cells are significantly defective in radiation-induced G1/S arrest. Phosphorylation of some ATM substrates has been shown to occur in NBS cells. It has, therefore, been concluded that Nbs1 checkpoint function is S phase specific. Here, we have compared NBS with A-T cell lines (AT-5762ins137) that express a low level of normal ATM protein to evaluate the impact of residual Nbs1 function in NBS cells. The radiation-induced cell cycle response of these NBS and 'leaky' A-T cells is almost identical; normal G2/M arrest after 2 Gy, intermediate G1/S arrest depending on the dose and an A-T-like S phase checkpoint defect. Thus, the checkpoint assays differ in their sensitivity to low ATM activity. Radiationinduced phosphorylation of the ATM-dependent substrates Chk2, RPAp34 and p53-Ser15 are similarly impaired in AT-5762ins137 and NBS cells in a dose dependent manner. In contrast, NBS cells show normal ability to activate ATM kinase following irradiation in vitro and in vivo. We propose that Nbs1 facilitates ATM-dependent phosphorylation of multiple downstream substrates, including those required for G1/S arrest.

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Section: H2ax Is Unique As Not Requiring Nbs1 Functionsupporting

confidence: 91%

Section: Examination Of Radiosensitivity and Cell Cycle Checkpoint Arsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 94%

See 2 more Smart Citations

Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest

et al. 2002

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“…The functional mutation of yMre11 disturbs both G1 and G2 arrest after exposure to ionizing radiation, implying the involvement of the X/M/R complex in G1 and G2 checkpoint control (Grenon et al, 2001). Similar to yeast, NBS1 could be involved in G1 checkpoint control (Jongmans et al, 1997;Matsuura et al, 1998b;Yamazaki et al, 1998;Antoccia et al, 1999) and G2 checkpoint regulation (Buscemi et al, 2001;Williams et al, 2002) after exposure to ionizing radiation. However, these defects in NBS cells are partial in nature, as is the case for intra-S phase checkpoints, so that the role of NBS1 in G1 and G2 checkpoint integrity has remained controversial.…”

Section: Nbs1 In Cell-cycle Checkpoint Controlmentioning

confidence: 99%

Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability

et al. 2002

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DNA double-strand breaks represent the most potentially serious damage to a genome and hence, at least two pathways of DNA repair have evolved; namely, homologous recombination repair and non-homologous end joining. Defects in both rejoining processes result in genomic instability including chromosome rearrangements, LOH and gene mutations, which may lead to development of malignancies. Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation that induces double-strand breaks, and high frequency of malignancies. NBS1, the product of the gene underlying the disease, forms a multimeric complex with hMRE11/ hRAD50 nuclease and recruits them to the vicinity of sites of DNA damage by direct binding to phosphorylated histone H2AX. The combination of the highlyconserved NBS1 forkhead associated domain and BRCA1 C-terminus domain has a crucial role for recognition of damaged sites. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. This process collaborates with cell-cycle checkpoints at S and G2 phase to facilitate DNA repair. NBS1 is also associated with telomere maintenance and DNA replication. Based on recent knowledge regarding NBS1, we propose here a two-step binding mechanism for damage recognition by repair proteins, and describe the molecular links to factors for genome stability.

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The Nijmegen breakage syndrome gene and its role in genome stability

et al. 2004

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NBS1 is the key regulator of the RAD50/MRE11/NBS1 (R/M/N) protein complex, a sensor and mediator for cellular DNA damage response. NBS1 potentiates the enzymatic activity of MRE11 and directs the R/M/N complex to sites of DNA damage, where it forms nuclear foci by interacting with phosphorylated H2AX. The R/M/N complex also activates the ATM kinase, which is a major kinase involved in the activation of DNA damage signal pathways. The ATM requires the R/M/N complex for its own activation following DNA damage, and for conformational change to develop a high affinity for target proteins. In addition, association of NBS1 with PML, the promyelocytic leukemia protein, is required to form nuclear bodies, which have various functions depending on their location and composition. These nuclear bodies function not only in response to DNA damage, but are also involved in telomere maintenance when they are located on telomeres. In this review, we describe the role of NBS1 in the maintenance of genetic stability through the activation of cell-cycle checkpoints, DNA repair, and protein relocation.

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Radiation Induction of p53 in Cells from Nijmegen Breakage Syndrome Is Defective but Not Similar to Ataxia-Telangiectasia

Cited by 44 publications

References 19 publications

Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest

Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest

Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability

The Nijmegen breakage syndrome gene and its role in genome stability

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