DNA-dependent Protein Kinase Activity Is Not Required for Immunoglobulin Class Switching

Bosma, Gayle C.; Kim, Jiyoon; Urich, Teresa; Fath, Donna M.; Cotticelli, M. Grazia; Ruetsch, Norman R.; Radic, Marko; Bosma, Melvin J.

doi:10.1084/jem.20001871

Cited by 94 publications

(89 citation statements)

References 80 publications

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“…Cell suspensions of BM and SPL were prepared and stained in the manner previously described (29,30). Cells were stained for CD43, CD45 (B220), IgM, IgM a , IgM b , IgD a , CD23, CD93, and V x using combinations of the following reagents: fluorescein (FL)-anti-CD43 (S7), allophycocyanin-anti-B220 (RA3-6B2), FL-anti-IgD a (AMS9.1), FL-anti-IgM (331.12), biotinanti-IgM (331.12), FL-anti-IgM a (RS3.1), biotin-anti-IgM b (AF6-78), biotin-anti-V x (10C5), Cy7PE-anti-CD23 (B3B4), and PE-anti-CD93 (AA4.1).…”

Section: Flow Cytometrymentioning

confidence: 99%

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Kiefer

Nakajima

Oshinsky

et al. 2008

The Journal of Immunology

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In response to encounter with self-Ag, autoreactive B cells may undergo secondary L chain gene rearrangement (receptor editing) and change the specificity of their Ag receptor. Knowing at what differentiative stage(s) developing B cells undergo receptor editing is important for understanding how self-reactive B cells are regulated. In this study, in mice with Ig transgenes coding for anti-self (DNA) Ab, we report dsDNA breaks indicative of ongoing secondary L chain rearrangement not only in bone marrow cells with a pre-B/B cell phenotype but also in immature/transitional splenic B cells with little or no surface IgM (sIgM−/low). L chain-edited transgenic B cells were detectable in spleen but not bone marrow and were still found to produce Ab specific for DNA (and apoptotic cells), albeit with lower affinity for DNA than the unedited transgenic Ab. We conclude that L chain editing in anti-DNA-transgenic B cells is not only ongoing in bone marrow but also in spleen. Indeed, transfer of sIgM−/low anti-DNA splenic B cells into SCID mice resulted in the appearance of a L chain editor (Vλx) in the serum of engrafted recipients. Finally, we also report evidence for ongoing L chain editing in sIgMlow transitional splenic B cells of wild-type mice.

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Section: Flow Cytometrymentioning

confidence: 99%

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Kiefer

Nakajima

Oshinsky

et al. 2008

The Journal of Immunology

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“…4). In this scheme, switching requires formation of AID-dependent DSBs, synapsis of upstream switch Sμ with downstream switch breaks mediated by H2AX/ 53BP1/ATM/Nbs1 (refs 6-8, 20-24) and NHEJ (Ku70/Ku80 and DNA-PKcs) 9,[16][17][18] . DNA lesions that remain unresolved initiate a p53-dependent checkpoint through the activation of ATM.…”

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confidence: 99%

“…DSB intermediates in the switch reaction are repaired by a nonhomologous end-joining (NHEJ) pathway requiring Ku80/Ku70 (refs 9, 16) and partially dependent on DNAPKcs 17,18 . To determine whether Ku80 is also required for c-myc-Igh translocations we overexpressed AID by retroviral transduction in immunoglobulin transgenic Ku80 −/− B cells stimulated with LPS and IL-4 (Ku80 −/− HL) 9 .…”

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confidence: 99%

Role of genomic instability and p53 in AID-induced c-myc–Igh translocations

Ramiro

Janković

Callén

et al. 2006

Nature

318

363

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Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies 1 . However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between cmyc and the IgH locus (Igh) are induced in primary B cells within hours of expression of the catalytically active form of activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosine to produce uracil in DNA 2,3 . Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks 4,5 . The pathway that mediates aberrant joining of c-myc and Igh differs from intrachromosomal repair during immunoglobulin class switch recombination in that it does not require histone H2AX 6 , p53 binding protein 1 (53BP1) 7,8 or the non-homologous end-joining protein Ku80 9 . In addition, translocations are inhibited by the tumour suppressors ATM, Nbs1, p19 (Arf) and p53, which is consistent with activation of DNA damage-and oncogenic stressinduced checkpoints during physiological class switching. Finally, we demonstrate that accumulation of AID-dependent, IgH-associated chromosomal lesions is not sufficient to enhance Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

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“…Ku70-and Ku80-deficient B cells have severely impaired CSR (Casellas et al, 1998;Manis et al, 1998;Reina-San-Martin et al, 2003), but this defect could result from a reduced cellular proliferative capacity or increased apoptosis of B cells rather than a CSR defect per se (Manis et al, 1998;Reina-SanMartin et al, 2003). Conflicting results were reported concerning the role of DNA-PKcs in CSR (Bosma et al, 2002;Manis et al, 2002a;Cook et al, 2003;Kiefer et al, 2007). Finally, Artemis deficiency does not seem to have any impact on CSR in such monoclonal B-cell mice (Rooney et al, 2005).…”

Section: Nhej and Csrmentioning

confidence: 96%

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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DNA-dependent Protein Kinase Activity Is Not Required for Immunoglobulin Class Switching

Cited by 94 publications

References 80 publications

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Role of genomic instability and p53 in AID-induced c-myc–Igh translocations

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

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