IgH Class Switch Recombination to IgG1 in DNA-PKcs-Deficient B Cells

Manis, John P.; Dudley, Darryll D.; Kaylor, Lianne; Alt, Frederick W.

doi:10.1016/s1074-7613(02)00306-0

Cited by 145 publications

(139 citation statements)

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“…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 .…”

mentioning

confidence: 99%

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

Ramiro

Janković

Callén

et al. 2006

Nature

320

366

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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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mentioning

confidence: 99%

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

Ramiro

Janković

Callén

et al. 2006

Nature

320

366

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“…DNA-PK is required for proper B-and T-cell antigen receptor rearrangement, and DNA-PK CS Ϫ/Ϫ mice develop severe combined immunodeficiency (30). Furthermore, Alt and colleagues have recently described a role for DNA-PK CS in immunoglobulin (Ig) class switching to the murine IgG2a isotype, an antibody subclass traditionally associated with cellmediated immune responses (39).…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Cleavage of the Catalytic Subunit of DNA-Dependent Protein Kinase during Poliovirus Infection

Graham

Gustin

Rivera

et al. 2004

J Virol

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DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinase that has critical roles in DNA double-strand break repair, as well as B-and T-cell antigen receptor rearrangement. The DNA-PK enzyme consists of the Ku regulatory subunit and a 450-kDa catalytic subunit termed DNA-PK CS . Both of these subunits are autoantigens associated with connective tissue diseases such as systemic lupus erythematosus (SLE) and scleroderma. In this report, we show that DNA-PK CS is cleaved during poliovirus infection of HeLa cells. Cleavage was visible as early as 1.5 h postinfection (hpi) and resulted in an approximately 40% reduction in the levels of native protein by 5.5 hpi. Consistent with this observation, the activity of the DNA-PK CS enzyme was also reduced during viral infection, as determined by immunoprecipitation kinase assays. Although it has previously been shown that DNA-PK CS is a substrate of caspase-3 in vitro, the protein was still cleaved during poliovirus infection of the caspase-3-deficient MCF-7 cell line. Cleavage was not prevented by infection in the presence of a soluble caspase inhibitor, suggesting that cleavage in vivo was independent of host caspase activation. DNA-PK CS is directly cleaved by a picornaviral 2A protease in vitro, producing a fragment similar in size to the cleavage product observed in vivo. Taken together, our results indicate that DNA-PK CS is cleaved by the 2A protease during poliovirus infection. Proteolytic cleavage of DNA-PK CS during poliovirus infection may contribute to inhibition of host immune responses. Furthermore, cleavage of autoantigens by viral proteases may target these proteins for the autoimmune response by generating novel, or "immunocryptic," protein fragments.

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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: 98%

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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IgH Class Switch Recombination to IgG1 in DNA-PKcs-Deficient B Cells

Cited by 145 publications

References 57 publications

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

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

Proteolytic Cleavage of the Catalytic Subunit of DNA-Dependent Protein Kinase during Poliovirus Infection

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

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