Reduced Switching in<i>SCID</i>B Cells Is Associated with Altered Somatic Mutation of Recombined S Regions

Cook, Adam J. L.; Oganesian, Liana; Harumal, Pearly; Basten, Antony; Brink, Robert; Jolly, Christopher J.

doi:10.4049/jimmunol.171.12.6556

Cited by 59 publications

(73 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, a potential DNA-PKcs function in CSR, not directly related to NHEJ, may be in the activation of the DSB response. However, DNA-PKcs kinase activity is not absolutely required for CSR, as evidenced by CSR (at reduced levels) to all isotypes in mice homozygous for the scid mutation, which generates a kinase-null form of DNA-PKcs (16,17,54). One interpretation of the latter finding, when compared with the more dramatic effects of the complete DNA-PKcs knockout on CSR, is that DNA-PKcs may have a CSR function independent of kinase activity.…”

Section: Discussionmentioning

confidence: 63%

“…All IgG isotypes and IgA were detected in serum isolated from Art N/N HL mice, although we observed variability in the actual amount of antibody among individual mice (data not shown). Both the variability and the reduced concentration of serum IgH isotypes has been observed previously in other models in which Ig knock-in alleles were used to rescue V(D)J recombination defects (12,16,17,38) and may reflect a lack of substantial numbers of peripheral T cells. In addition, serum levels of IgH isotypes are influenced by additional factors including mouse age and infection status (6).…”

Section: Knock-in Igh and Ig Light Chain Alleles Rescue B Cell Develomentioning

confidence: 83%

“…However, HL-reconstituted DNA-PKcs-null (DP-T͞HL) B cells are defective for CSR to all IgH isotypes except IgG1, despite a lack of growth defects (15), whereas HL-reconstituted severe combined immunodeficiency (DNA-PKcs kinase-inactive) B cells also show CSR defects, albeit more modest ones (16,17). Based on these findings, one might speculate that the DNA-PK holoenzyme plays a similar role in CSR as it does in V(D)J recombination.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Rooney

Alt

Sekiguchi

et al. 2005

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

View full text Add to dashboard Cite

Assembly of Ig genes in B lineage cells involves two distinct DNA rearrangements. In early B cell development, site-specific double strand breaks (DSBs) at germ-line V, D, and J gene segments are joined via nonhomologous end-joining (NHEJ) to form variable region exons. Activated mature B cells can change expressed Ig heavy chain constant region exons by class switch recombination (CSR), which also involves DSB intermediates. Absence of any known NHEJ factor severely impairs joining of cleaved V, D, and J segments. In NHEJ, DNA-dependent protein kinase (DNA-PK), which is comprised of the Ku70͞80 end-binding heterodimer and the catalytic subunit (DNA-PKcs), activates Artemis to generate a nuclease that processes DSBs before ligation. Because inactivation of DNA-PKcs components also severely affects CSR, we tested whether DNA-PK also functions in CSR via activation of Artemis. To obviate the requirement for V(D)J recombination, we generated DNA-PKcs-and Artemis-deficient B cells that harbored preassembled Ig heavy chain and -light chain ''knock-in'' (HL) alleles. We found that Artemis-deficient HL B cells undergo robust CSR, indicating that DNA-PKcs functions in CSR via an Artemis-independent mechanism. To further elucidate potential Artemis-independent functions of DNA-PKcs, we asked whether the embryonic lethality associated with double-deficiency for DNA-PKcs and the related ataxia-telangiectasia-mutated (ATM) kinase was also observed in mice doubly deficient for ATM and Artemis. We found that ATM͞Artemis double-deficient mice were viable and born in normal Mendelian numbers. Therefore, we conclude that DNA-PKcs has Artemis-independent functions in CSR and normal development.ATM ͉ DNA-PKcs P recursor B and T cells assemble antigen receptor genes from component, germ-line V, D, and J segments via V(D)J recombination (1). V(D)J recombination is initiated by the lymphoid-specific RAG1͞2 endonuclease (RAG), which introduces DNA double strand breaks (DSBs) between V(D)J coding sequences and f lanking recombination signal (RS) sequences. RAG cleavage generates two distinct intermediates: hairpin coding ends and blunt RS ends, which are then fused via the nonhomologous end-joining (NHEJ) pathway of DSB repair (2). There are six known mammalian NHEJ factors (2).

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Knock-in Igh and Ig Light Chain Alleles Rescue B Cell Develomentioning

confidence: 83%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Rooney

Alt

Sekiguchi

et al. 2005

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

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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...

show abstract

“…Given the reduced proliferative capacity of B cells from Ku70/80-deficient animals, it cannot be established with certainty that the CSR defect seen in these animals does not merely reflect this diminished proliferative capacity. Likewise, an absolute requirement for DNA-PKcs during CSR remains a debatable matter as CSR is variably impaired depending on the DNA-PKcs-deficiency model used for these studies [50][51][52][53]. Even in mice with null DNA-PKcs alleles, CSR is abrogated to all isotypes except for that of IgG1 [50].…”

mentioning

confidence: 99%

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

View full text Add to dashboard Cite

B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...

show abstract

Reduced Switching inSCIDB Cells Is Associated with Altered Somatic Mutation of Recombined S Regions

Abstract: Material

Cited by 59 publications

References 66 publications

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

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

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

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

Contact Info

Product

Resources

About