Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development

Rooney, Sean; Alt, Frederick W.; Sekiguchi, JoAnn; Manis, John P.

doi:10.1073/pnas.0409857102

Cited by 45 publications

(46 citation statements)

References 61 publications

(88 reference statements)

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“…27,28 We developed a conditional Artemis KO mouse model resulting in the deletion of Artemis DNA repair factor specifically in mature B cells to more directly analyze the role of Artemis during CSR in an otherwise physiologic immune system (polyclonal B cells and the presence of T lymphocytes). We conclude from our analyses that, although Artemis is not essential for an efficient CSR to occur, as previously noted by Rooney et al, 24 it most probably intervenes in the resolution of a subset of DNA breaks generated during CSR, which is in accord with the recent observation of persistent DNA breaks at IgH loci in Artemis KO mice carrying IgH/L transgenes. 29 Artemis is a DNA endonuclease/exonuclease whose function is critical to resolve DNA hairpin structures at coding ends during V(D)J recombination and process a subset of DNA modifications introduced by ionizing radiations or radiomimetic drugs, such as bleomycin.…”

supporting

confidence: 75%

“…Rooney et al developed an Artemis-deficient mouse in which the development of mature B cells is rescued by the knock-in of heavy and light chain Ig loci to show that CSR is not impaired in these Artemis-deficient monoclonal B cells. 24 On the other hand, conflicting results were obtained on the role of DNA-PK catalytic subunit (DNA-PKcs) on CSR using either DNA-PKcs KO or mutated (scid) mice. [25][26][27][28] More recently, Franco et al used a sophisticated fluorescence in situ hybridization approach to demonstrate the persistence of AIDdependent DNA-DSB at the IgH locus in the context of either DNA-PKcs or Artemis deficiency, paving the way to a role for Artemis during CSR.…”

Section: Introductionmentioning

confidence: 99%

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Reduced immunoglobulin class switch recombination in the absence of Artemis

Rivera-Munoz

Soulas-Sprauel

Guyader

et al. 2009

Blood

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IntroductionThe large diversity of antigen receptors on T and B cells is provided in lymphoid organs by different mechanisms. The first one, the V(D)J recombination, allows for the somatic rearrangement of V (variable), D (diversity), and J (joining) gene loci into V(D)J segments coding for the variable antigen recognition domain of B-cell receptors and T-cell receptors. 1,2 This process is initiated by Rag (recombination acting gene) 1 and 2 endonuclease, which introduces DNA double-strand breaks (DSBs) between V, D, and J coding segments and flanking recombination signal sequences, thereby generating hairpin-sealed DNA coding ends on the chromosome and blunt signal ends excised from the chromosome. The repair of the DSBs is then ensured by the general DNA repair machinery, composed of at least 7 known factors of the nonhomologous end-joining (NHEJ) pathway: Ku70, Ku80, DNA-PKcs, Artemis (Art), XRCC4, Cernunnos/XLF, and DNA ligase IV. The DSB is recognized by the Ku70/Ku80 heterodimer, which recruits DNA-PKcs to form the DNA-PK complex. DNA-PKcs, a DNA-dependent PI3 kinase, recruits and activates Artemis by a phosphorylation process. Artemis is a 5Ј-3Ј exonuclease, which acquires an endonucleolytic activity on 5Ј and 3Ј overhangs as well as DNA hairpins on activation by DNA-PKcs in vitro whose function during V(D)J recombination is to open the hairpin-sealed coding ends. 3 Mutations in genes coding for NHEJ factors are responsible for the onset of various types of severe combined immunodeficiencies (SCID) in humans. [4][5][6][7] NHEJ represents the major DNA-DSB repair pathway in mammalian cells, and these patients present a cellular hypersensitivity to ionizing radiations (radiosensitive, RS-SCID). Similarly, NHEJ factor gene inactivation in mice results in a profound impaired B-and T-cell development. [8][9][10][11][12][13][14] After completion of V(D)J recombination, mature immunoglobulin M ϩ (IgM ϩ ) B cells migrate to secondary lymphoid organs, where the immune B-cell repertoire is further shaped by 2 independent processes: somatic hypermutation and class switch recombination (CSR), which enhances the affinity and modifies the effector function of antibodies, respectively, without altering their antigenic specificity. CSR results in the replacement of the IgM constant region (C) with one of the downstream C H gene (␥, ⑀, or ␣) by a recombination mechanism between large repetitive switch (S) regions located upstream each constant region (except ␦), allowing for the fusion of the 2 S regions and excision of intervening DNA. 15,16 The B-cell-specific activation-induced cytidine deaminase factor (AID) initiates the CSR reaction by deaminating cytidine residues to uracil within S regions in a transcriptiondependent manner, leading to DNA breaks in the 2 opposite strands of DNA. 17,18 Much experimental evidence supports the generation of DSBs during CSR, 15 although the exact molecular mechanism by which the initial AID-mediated DNA lesion is further processed to DNA-DSB is not yet fully understood. 19 As NHEJ r...

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supporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Reduced immunoglobulin class switch recombination in the absence of Artemis

Rivera-Munoz

Soulas-Sprauel

Guyader

et al. 2009

Blood

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“…It was thought that because hairpins are not generated in CSR, Artemis does not play a role in this process 24. Therefore the role of the DNA–PK complex in CSR was considered to be in regulating end processing, possibly by phosphorylating other proteins 25.…”

Section: Mechanisms Of Recombination In Lymphoid Cellsmentioning

confidence: 99%

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Procházková

Loizou

2015

Immunology

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SummaryIn recent years, several novel congenital human disorders have been described with defects in lymphoid B‐cell and T‐cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double‐strand break repair, as well as compromised DNA damage‐induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways.

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“…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). Although some key NHEJ components seem to be required for CSR, one cannot exclude a role outside of NHEJ per se for these factors.…”

Section: Nhej and Csrmentioning

confidence: 94%

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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Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development

Cited by 45 publications

References 61 publications

Reduced immunoglobulin class switch recombination in the absence of Artemis

Reduced immunoglobulin class switch recombination in the absence of Artemis

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

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

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