53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination

Manis, John P.; Morales, Julio C.; Xia, Zuo‐Li; Kutok, Jeffery L.; Alt, Frederick W.; Carpenter, Phillip B.

doi:10.1038/ni1067

Cited by 303 publications

(341 citation statements)

References 49 publications

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“…In activated mature B cells, specific DSBs are introduced into the immunoglobulin heavy chain (IgH) locus during IgH class-switch recombination (CSR) which involves the exchange of IgH constant region exons (Chaudhuri and Alt, 2004;Manis et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies indicate that 53BP1 is required for IgH CSR in normal activated B cells (Manis et al, 2004). 53BP1 has also been implicated in precancerous lesions in which aberrant cellular proliferation triggers DNA replication stress, the formation of DNA DSBs and the localization of 53BP1 to discrete nuclear foci (Gorgoulis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas

et al. 2007

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p53-Binding protein 1 (53BP1) encodes a critical checkpoint protein that localizes to sites of DNA double-strand breaks (DSBs) and participates in DSB repair. Mice that are 53bp1 deficient or hemizygous have an increased incidence of lymphoid malignancies. However, 53BP1 abnormalities in primary human tumors have not been described. By combining high-density single nucleotide polymorphism (HD SNP) array data and gene expression profiles, we found 9 of 63 newly diagnosed human diffuse large B-cell lymphomas (DLBCLs) with single copy loss of the chromosome 15q15 region including the 53BP1 locus; these nine tumors also had significantly lower levels of 53BP1 transcripts. 53BP1 single copy loss found with the HD SNP array platform was subsequently confirmed by fluorescence in situ hybridization. These studies highlight the role of 53BP1 copy loss in primary human DLBCLs and the value of integrative analyses in detecting this genetic lesion in human tumors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas

et al. 2007

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“…As eluded to in the introduction, experimental evidence has demonstrated that CSR, like V(D)J recombination, involves the generation of DNA dsb: (1) an episomal circle is generated during CSR (Chaudhuri and Alt, 2004); (2) AID-dependent DNA dsb have been detected by ligated mediated PCR assays in Switch regions of mitogen-activated B cells (Wuerffel et al, 1997;Catalan et al, 2003;Rush et al, 2004); (3) phosphorylation of histone H2AX (gH2AX), which spreads around DNA dsb, is detected at the IgH locus in an AID-dependent manner, in B cells activated for CSR (Petersen et al, 2001); (4) CSR is impaired in mice deficient for H2AX, ATM, p53 binding protein 1 and Nbs1, which are DDR early components (Reina-San-Martin et al, 2003, 2004Lumsden et al, 2004;Manis et al, 2004;Ward et al, 2004;Kracker et al, 2005). The link between AIDdriven DNA cytidine deamination and the introduction of DNA dsb in Ig S regions is not fully established yet.…”

Section: Nhej and Csrmentioning

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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“…In contrast to V(D)J recombination, CSR is nearly completely dependent on 53BP1 (Manis et al, 2004;Ward et al, 2004;Reina-San-Martin et al, 2007), but only mildly defective in mice lacking Nbs1, ATM or H2AX (Celeste et al, 2002;Reina-San-Martin et al, 2003Lumsden et al, 2004;Kracker et al, 2005). Although the precise function of ATM, 53BP1, H2AX and Nbs1 in the repair of CSR breaks remains to be defined, we have proposed that these proteins stabilize the synapsis of distal switch regions, potentially by modification of chromatin structure at sites of AID-dependent damage .…”

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confidence: 99%

“…However, the defect is less severe than in ATM À/À mice, and Nbs1, H2AX and 53BP1-deficient mice are not highly prone to spontaneous lymphomas (Bassing et al, 2003;Celeste et al, 2003;Difilippantonio et al, 2005;Ward et al, 2005;Morales et al, 2006). Moreover, in contrast to ATM knockouts, no impairment in the joining of V(D)J recombination associated breaks have been detected in H2AX À/À and 53BP1 À/À mice (Bassing et al, 2002;Manis et al, 2004;Ward et al, 2004).…”

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confidence: 99%

Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly

Callén

Nussenzweig

2007

Oncogene

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Double-strand breaks (DSBs) are intermediates in several physiological processes including V(D)J and class switch recombination. They are also potent substrates for chromosomal translocations that arise as by-products of antigen receptor gene assembly in lymphocytes. ATM is one among several key proteins involved in the detection, signaling and repair of DNA breaks. Despite redundancies in DSB signaling pathways, it has recently been demonstrated that ATM deficient lymphocytes can survive and proliferate several generations in vitro and in vivo despite harboring terminally deleted chromosomes produced by V(D)J recombination. In this review, we discuss how two complementary genome maintenance functions mediated by ATM prevent lymphocytes from adapting to persistent DNA damage.

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53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination

Cited by 303 publications

References 49 publications

Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas

Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas

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

Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly

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