Alternative end joining during switch recombination in patients with Ataxia-Telangiectasia

Pan, Qiang; Petit-Frère, Corinne; Lähdesmäki, Aleksi; Gregorek, Hanna; Chrzanowska, Krystyna; Hammarström, Lennart

doi:10.1002/1521-4141(200205)32:5<1300::aid-immu1300>3.0.co;2-l

Cited by 104 publications

(115 citation statements)

References 45 publications

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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. The class switch pathway is mediated by NHEJ proteins (Manis et al, 2002) and also includes the mismatch-repair proteins such as Mlh1, Msh2 and Pms2 (Ehrenstein et al, 2001).…”

Section: Indispensable Role Of Nbs1 In Vertebrate Homologous Recominamentioning

confidence: 71%

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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Section: Indispensable Role Of Nbs1 In Vertebrate Homologous Recominamentioning

confidence: 71%

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

et al. 2002

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“…Unique Sm-Sa1 sequences, representing independent CSR events, were subsequently compared with Sm and Sa junctions (n ¼ 154) from healthy adult controls. 30,31 Previously described Artemis-deficient patients showed a strong dependence on long microhomologies and a complete lack of 'direct end-joining'. 23 The average length of microhomology, defined as successive nucleotides that were shared by both the Sm and Sa regions at the CSR junctions, was not significantly different from control in patient 1 (3.8 ± 5.2 bp versus 1.8±3.2 bp in controls) and in patient 2 (2.0±2.7 bp versus 1.8 ± 3.2 bp in controls).…”

Section: Effect Of the Artemis Mutations On Csrmentioning

confidence: 99%

“…The amplification of Sm-Sa fragments from in vivo S cells was performed, as described previously, 30,48 except that a modified version of Taq polymerase (Go Taq, Promega) was used in the PCR reactions. With this modification, a 2-4-fold increase in sensitivity was achieved.…”

Section: Radiation Sensitivity Assaysmentioning

confidence: 99%

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Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

IJspeert

Lankester

et al. 2011

Genes Immun

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Artemis deficiency is known to result in classical TÀBÀ severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical TÀBÀ SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5 0 splice-site or an intronic point mutation creating a novel 3 0 splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3 0 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

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“…Commonly reported cellular defects include a low proportion of helper CD4 ϩ T cells, decreased CD4 ϩ ͞CD8 ϩ ratio, defective T cell proliferation, and chromosomal translocations (including those involving antigen receptor genes) in mitogen stimulated T cells. NBS patients also display deficiencies in serum IgA and IgG4, suggesting a defect in CSR (29,30). However, impaired helper T cell function could also contribute to the reduction in switched isotypes in these patients.…”

mentioning

confidence: 99%

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1

Reina‐San‐Martin

Nussenzweig

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

128

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Mre11, Rad50, and Nbs1 form an evolutionarily conserved protein complex (Mre11-Rad50 -Nbs1, MRN) that has been proposed to function as a DNA damage sensor. Hypomorphic mutations in Mre11 and Nbs1 result in the human ataxia-telangiectasia-like disorder and Nijmegen breakage syndrome (NBS), respectively. In contrast, complete inactivation of Mre11, Rad50, or Nbs1 leads to early embryonic lethality, suggesting that the hypomorphic mutations may fail to reveal some of the essential functions of MRN. Here, we use Cre-loxP-mediated recombination to restrict Nbs1 deletion to B lymphocytes. We find that disruption of Nbs1 results in the accumulation of high levels of spontaneous DNA damage, impaired proliferation, and chromosomal endoreduplication. Moreover, we show that Ig class-switch recombination (CSR) is diminished in Nbs1-deficient B cells. The CSR defect is B cellintrinsic, independent of switch-region transcription, and a consequence of inefficient recombination at the DNA level. Our findings reveal that Nbs1 is critical for efficient Ig CSR and maintenance of the integrity of chromosomal structure and number.

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Alternative end joining during switch recombination in patients with Ataxia-Telangiectasia

Cited by 104 publications

References 45 publications

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

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

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1

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