A Human Severe Combined Immunodeficiency (SCID) Condition with Increased Sensitivity to Ionizing Radiations and Impaired V(D)J Rearrangements Defines a New DNA Recombination/Repair Deficiency

Nicolas, Nathalie; Moshous, Despina; Cavazzana, Marina; Papadopoulo, Dora; Chasseval, Régina de; Deist, Françoise Le; Fischer, Alain; Villartay, Jean‐Pierre de

doi:10.1084/jem.188.4.627

Cited by 142 publications

(92 citation statements)

References 51 publications

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“…Sequencing analysis of several junctions revealed a normal pattern of deletions and N nucleotide addition as compared to normal control lymphocytes (Table 3), without any evidence for an obvious qualitative V(D)J recombination defect, despite the fact that Lig4 is one of the major players in V(D)J recombination. We subsequently tested V(D)J recombination in vitro by using extrachromosomal recombination substrates introduced into P-1 0 s fibroblasts as described [15,16]. The overall recovery of coding-and signal joints was normal as compared to a normal control.…”

Section: V(d)j Recombination Ex Vivo and In Vitromentioning

confidence: 99%

“…This study was approved by the (INSERM) Institutional Review Board. SV40-transformed fibroblast cell lines were generated by transfection of the SV40 large T antigen encoding plasmid pLAS-WT and by overgrowth of transformed cells over nontransformed fibroblasts without other means of selection as described [15]. Human telomerase immortalized fibroblasts were obtained by transfecting the SV40 transformed fibroblasts with a hTRT expression construct (pGRN145) and by isolating clones under neomycin selection as previously described [34].…”

Section: Cellsmentioning

confidence: 99%

“…Patients of the first group exhibit mutations in the lymphoid-specific factors RAG1 or RAG2 [14]. The second group is additionally characterized by increased cellular sensitivity to ionizing radiations (IR), which points to a general DNA repair deficiency [15]. This radiosensitive SCID (RS-SCID) is caused by null mutations in the V(D)J/NHEJ factor Artemis [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

et al. 2005

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DNA double-strand breaks (dsb) during V(D)J recombination of T and B lymphocyte receptor genes are resolved by the non-homologous DNA end joining pathway (NHEJ) including at least six factors: Ku70, Ku80, DNA-PK cs , Artemis, Xrcc4, and DNA ligase IV (Lig4). Artemis and Lig4 are the only known V(D)J/NHEJ factors found deficient in human genetic disorders. Null mutations of the Artemis gene result in a complete absence of T and B lymphocytes and increased cellular sensitivity to ionizing radiations, causing radiosensitive-SCID. Mutations of Lig4 are exclusively hypomorphic and have only been described in six patients, four exhibiting mild immunodeficiency associated with microcephaly and developmental delay, while two patient had leukemia. Here we report a SCID associated with microcephaly caused by compound heterozygous hypomorphic mutations in Lig4. Residual activity of Lig4 in these patients is underscored by a normal pattern of TCR-a and -b junctions in the T cells of the patients and a moderate impairment of V(D)J recombination as tested in vitro. These observations contrast with the severity of the clinical immunodeficiency, suggesting that Lig4 may have additional critical roles in lymphocyte survival beyond V(D)J recombination.

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Section: V(d)j Recombination Ex Vivo and In Vitromentioning

confidence: 99%

Section: Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

et al. 2005

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“…RS-SCID was described as a phenotype in a number of immunodeficiency patients but identifying the defective gene(s) progressed slowly [52][53][54]. The identification of mutations in DCLRE1C/Artemis was the next genetic defect for RS-SCID to be identified, facilitated by its occurrence within a community of Athabascan America Indians (see below for further details) [55].…”

Section: Xlf/cernunnos Defective Patientsmentioning

confidence: 99%

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

2014

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Double strand break repair V(D)J recombination (Severe) combined immunodeficiency -(S)CID Human syndromes a b s t r a c t DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency -(S)CID -due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology.

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“…Rag1 and Rag2 genes (Nicolas et al, 1998;Moshous et al, 2000). Despite the strong similarity of RS-SCID patients and scid mice, DNA-PK activity is normal in these patients and the implication of the DNA-PKcs gene has been ruled out by genetic means in several families (Nicolas et al, 1996).…”

Section: Artemismentioning

confidence: 99%

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

et al. 2007

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The immune system is the site of intense DNA damage/ modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the nonhomologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways. Oncogene (2007) 26, 7780-7791; doi:10.1038/sj.onc.1210875 Keywords: V(D)J recombination; class switch recombination; SCID; Artemis; Cernunnos; NHEJ V(D)J recombination and CSR: two rearrangement processes that shape the immune system repertoire B and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the B-cell receptor and T-cell receptor, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Figure 1) which assembles previously scattered Variable (V), Diversity (D) and Joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism (Tonegawa, 1983). The reaction is initiated by the lymphoid-specific factors, Rag1 and Rag2, which recognize recombination signal sequences (RSS) that flank all V, D and J gene units and introduce a DNA dsb at the border of the RSS (see Dudley et al. (2005) for a review on V(D)J recombination). The resulting DNA double-strand break (DNA dsb) is resolved by the ubiquitous DNA repair machinery known as non-homologous end-joining (NHEJ). The convergent efforts of scientists in the immunology and DNA repair fields were decisive in defining the various actors and molecular mechanisms of this DNA repair pathway over the years as will be discussed below.The terminal maturation of B lymphocytes, which occurs in germinal centres of secondary lymphoid organs upon antigen recognition, is accompanied by two additional molecular processing of immunoglobulin genes that increase the efficiency of the humoral response: (1) the class switch recombination (CSR, Figure 2) exchanges the immunoglobulin (Ig) constant region (CH), thus modifying the function of the Ig without altering its antigenic specificity (Manis et al., 2002b) and (2) somatic hypermutations are introduced in the Ig variable domains, thus increasing their affinity for antigen (Papavasiliou and Schatz, 2002). These two events ar...

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A Human Severe Combined Immunodeficiency (SCID) Condition with Increased Sensitivity to Ionizing Radiations and Impaired V(D)J Rearrangements Defines a New DNA Recombination/Repair Deficiency

Cited by 142 publications

References 51 publications

Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

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