Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome

Harfst, Eva; Cooper, Stephen D.; Neubauer, Susann; Distel, Luitpold; Grawunder, Ulf

doi:10.1016/s0161-5890(01)00008-6

Cited by 62 publications

(35 citation statements)

References 49 publications

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“…However, in chicken DT40 cells with a targeted disruption of the NBS1 gene, the NBS1 deficient cells showed indistinguishable NHEJ events from those wild-type cells, as measured by a plasmid DNA end joining assay in vivo [9]. This is consistent with the observation that in cells from NBS patient carrying a mutated NBS1 gene, the V(D)J recombination frequencies and the quality of signal and coding joining are comparable to wild-type controls [37]. The role of NBS1 in NHEJ is rather controversial when considering results obtained in vitro and in vivo, or in chicken and human cells, as mentioned above.…”

Section: Mre11supporting

confidence: 85%

The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control

Zhang

Zhou

Lim³

2006

Cell Res

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The genomes of eukaryotic cells are under continuous assault by environmental agents and endogenous metabolic byproducts. Damage induced in DNA usually leads to a cascade of cellular events, the DNA damage response. Failure of the DNA damage response can lead to development of malignancy by reducing the efficiency and fidelity of DNA repair. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex (MRN) that plays a critical role in the cellular response to DNA damage and the maintenance of chromosomal integrity. Mutations in the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS), a hereditary disorder that imparts an increased predisposition to development of malignancy. The phenotypic characteristics of cells isolated from NBS patients point to a deficiency in the repair of DNA double strand breaks. Here, we review the current knowledge of the role of NBS1 in the DNA damage response. Emphasis is placed on the role of NBS1 in the DNA double strand repair, modulation of the DNA damage sensing and signaling, cell cycle checkpoint control and maintenance of telomere stability.

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Section: Mre11supporting

confidence: 85%

The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control

Zhang

Zhou

Lim³

2006

Cell Res

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“…In contrast to our fi ndings, previous studies of V(D)J recombination in fi broblasts from patients that express hypomorphic Nbs1 alleles and mouse embryonic fi broblasts that are defi cient in Mre11 failed to reveal defects in coding joint formation ( 56,58,66 ). Importantly, these analyses assessed the repair of Rag-mediated DSBs generated on extrachromosomal plasmid recombination substrates in nonlymphoid cells, whereas we analyzed the repair of chromosomal Ragmediated DSBs in developing lymphocytes and lymphocyte cell lines.…”

Section: Generation Of Nbs1 M/m and Mre11 Atld1/atld1 Abl Pre-b Cellscontrasting

confidence: 79%

MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks

Helmink¹,

Bredemeyer²,

Lee³

et al. 2009

J Cell Biol

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“…This is supported by evidence that V(D)J recombination, which is known to be mediated by NHEJ, is quite normal in NBS patients (Harfst et al, 2000). The N/M/R complex is required for Ig class switch recombination (Pan et al, 2002;van Engelen et al, 2001;Petersen et al, 2001) and this might provide us with an explanation of why NBS patients are immunodeficient.…”

Section: Indispensable Role Of Nbs1 In Vertebrate Homologous Recominamentioning

confidence: 70%

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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Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome

Cited by 62 publications

References 49 publications

The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control

The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control

MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks

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

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