AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH Translocations

Robbiani, Davide F.; Bothmer, Anne; Callén, Elsa; Reina‐San‐Martin, Bernardo; Dorsett, Yair; Difilippantonio, Simone; Bolland, Daniel J.; Chen, Hua Tang; Corcoran, Anne E.; Nussenzweig, André; Nussenzweig, Michel C.

doi:10.1016/j.cell.2008.09.062

Cited by 412 publications

(421 citation statements)

References 80 publications

(144 reference statements)

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“…MYC-IGH and BCL6-IGH translocations are found in a variety of human mature B cell lymphomas, such as Burkitt's lymphomas and DLBCL. AID initiates DSBs at the mouse MYC locus for the MYC-IGH translocation during the murine germinal-center B cell stage (23)(24)(25). It has recently become clear that AID targets DNA motifs in the human MYC-IGH and BCL6-IGH translocations as well (5).…”

Section: Resultsmentioning

confidence: 99%

Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

Lieber

Tsai

et al. 2015

Molecular and Cellular Biology

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Chromosomal translocations are a hallmark of hematopoietic malignancies. CG motifs within translocation fragile zones (typically 20 to 600 bp in size) are prone to chromosomal translocation in lymphomas. Here we demonstrate that the CG motifs in human translocation fragile zones are hypomethylated relative to the adjacent DNA. Using a methyltransferase footprinting assay on isolated nuclei (in vitro), we find that the chromatin at these fragile zones is accessible. We also examined in vivo accessibility using cellular expression of a prokaryotic methylase. Based on this assay, which measures accessibility over a much longer time interval than is possible with in vitro methods, these fragile zones were found to be more accessible than the adjacent DNA. Because DNA within the fragile zones can be methylated by both cellular and exogenous methyltransferases, the fragile zones are predominantly in a duplex DNA conformation. These observations permit more-refined models for why these zones are 100-to 1,000-fold more prone to undergo chromosomal translocation than the adjacent regions.C hromosomal translocations are seminal events in the development of many hematologic malignancies (1). Many hematopoietic malignancies are associated with recurrent reciprocal translocations and their resulting gene fusions or amplifications, which guide diagnosis, assessment of prognosis, and treatment. One example is the BCL2-IGH translocation, t(14;18)(q32;q21), observed in 85% of follicular lymphomas (FL) and 30% of diffuse large B cell lymphomas (DLBCL). A second example is the CCND1-IGH translocation, t(11;14)(q13;q32), observed in almost all mantle cell lymphomas (MCL). Oncogenes near sites of recurrent translocation often confer a selective growth advantage (2). For unknown reasons, human chromosomal translocation breakpoints near these oncogenes frequently cluster within tight DNA zones (often only 20 to 600 bp in length) known as fragile zones (see the green starbursts in the upper portion of Fig. 1A and 2A). These zones are 100-to 1,000-fold more sensitive to breakage than the adjacent DNA regions located, for example, only 20 bp to either side of the fragile zone (2-7). Hence, the DNA sequences surrounding each oncogene are not equally sensitive to breakage. The molecular basis for such an extreme breakage propensity within such a short zone of DNA is unknown, despite our progress on elucidation of other aspects of the mechanism described below (8).We have previously reported that breakpoints of human lymphoid translocation fragile zones are not randomly distributed (Fig. 1A and 2A). Pro-B/pre-B cell-stage translocations show a breakage propensity for the CG (commonly called CpG but designated CG in this paper) DNA sequence motif within the 20 to 600-bp fragile zones (3). We have proposed a model in which activation-induced deaminase (AID) initiates double-strand breaks (DSBs) by acting at the methylated form of these CG sites in single-stranded DNA (ssDNA) to deaminate the 5-methylcytosine to yield a T-G mismatch (3). The r...

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Section: Resultsmentioning

confidence: 99%

Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

Lieber

Tsai

et al. 2015

Molecular and Cellular Biology

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“…To determine whether AID is the source of dsDNA breaks in Igβ that lead to Igβ/IgH translocations, we made use of mice that carry an I-SceI site in IgH (IgH I/I ) (26). I-SceI is an endonuclease that recognizes an 18-bp site that is not normally present in the mouse genome (54).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to somatic mutations, AID also produces doublestrand breaks in IgH and at c-myc (26). As a result, AID creates substrates for c-myc/IgH translocations (27)(28)(29).…”

mentioning

confidence: 99%

Role of the translocation partner in protection against AID-dependent chromosomal translocations

Janković

Robbiani

Dorsett

et al. 2009

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

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Chromosome translocations between Ig (Ig) and non-Ig genes are frequently associated with B-cell lymphomas in humans and mice. The best characterized of these is c-myc/IgH translocation, which is associated with Burkitt's lymphoma. These translocations are caused by activation-induced cytidine deaminase (AID), which produces double-strand DNA breaks in both genes. c-myc/IgH translocations are rare events, in part because ATM, p53, and p19 actively suppress them. To further define the mechanism of protection against the accumulation of cells that bear c-myc/IgH translocation, we assayed B cells from mice that carry mutations in cell-cycle and apoptosis regulator proteins that act downstream of p53. We find that PUMA, Bim, and PKCδ are required for protection against c-myc/ IgH translocation, whereas Bcl-XL and BAFF enhance c-myc/IgH translocation. Whether these effects are general or specific to cmyc/IgH translocation and whether AID produces dsDNA breaks in genes other than c-myc and Ig is not known. To examine these questions, we developed an assay for translocation between IgH and Igβ, both of which are somatically mutated by AID. Igβ/IgH, like c-myc/IgH translocations, are AID-dependent, and AID is responsible for lesions on IgH and the non-IgH translocation partners. However, ATM, p53, and p19 do not protect against Igβ/IgH translocations. Instead, B cells are protected against Igβ/IgH translocations by a BAFF-and PKCδ-dependent pathway. We conclude that AIDinduced double-strand breaks in non-Ig genes other than c-myc lead to their translocation, and that at least two nonoverlapping pathways protect against translocations in primary B cells.M ature B-cell lymphomas are frequently associated with chromosomal translocations between Ig loci and non-Ig genes. The latter include c-myc in Burkitt's lymphoma, bcl-2 in follicular lymphoma, bcl-6 in diffuse large-cell lymphoma, and FGFR in multiple myeloma (1-3). These translocations are believed to be important for malignant transformation because they can deregulate the transcription of oncogenes by placing them under the control of the Ig transcriptional elements.Translocations are thought to be particularly prevalent in B-cell lymphomas because B cells undergo a series of DNA remodeling reactions that involve obligate double-strand breaks (DSBs) in Ig loci. V(D)J recombination is the first of these reactions, and is mediated by the RAG1/2 endonuclease (4, 5). This enzyme produces paired hairpin and blunt DNA ends when it cuts recombination signal sequences during antigen receptor gene assembly in developing B-cell precursors (6, 7). Class switch recombination (CSR) and somatic hypermutation (SHM) remodel Ig genes in mature B cells activated during immune responses. CSR is a DNA recombination reaction that alters the effector function of the antibody by replacing one constant region with another without altering the antigen-binding variable region. In contrast to V(D)J recombination, CSR is not sequence-specific but instead regionspecific, resulting in recombinati...

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“…By contrast, the mechanisms giving rise to many chromosomal translocations in lymphoid malignancies are believed to be the result of illegitimate lymphoid-specific recombination mechanisms, such as V(D)J 16,34,40,41 or class switch recombination. 11,42 In this study, we aimed to determine whether there were any consistent differences between t(9;22) breakpoints in CML and ALL, and to understand why the p190 fusion is nearly always associated with lymphoid disease. We characterized 82 forward BCR-ABL genomic breakpoints and 54 reverse ABL-BCR genomic breakpoints using LT-PCR and identified 11 cases with large 9q þ deletions by MLPA ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…3 The mechanisms behind many chromosomal translocations in lymphoid malignancies are clearer and are believed to be the result of the aberrant activity of the machinery for V(D)J or class switch recombination. 11,12 In V(D)J recombination, which takes place early in B-cell differentiation, the recombinaseactivating gene (RAG) enzyme complex recognises specific recombination signal sequences (RSSs) flanking the V(D)J segments. RAG makes specific double stranded breaks that are subsequently ligated by NHEJ into a coding joint and a signal joint.…”

Section: Introductionmentioning

confidence: 99%

Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation

et al. 2010

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We sought to understand the genesis of the t(9;22) by characterizing genomic breakpoints in chronic myeloid leukemia (CML) and BCR-ABL-positive acute lymphoblastic leukemia (ALL). BCR-ABL breakpoints were identified in p190 ALL (n ¼ 25), p210 ALL (n ¼ 25) and p210 CML (n ¼ 32); reciprocal breakpoints were identified in 54 cases. No evidence for significant clustering and no association with sequence motifs was found except for a breakpoint deficit in repeat regions within BCR for p210 cases. Comparison of reciprocal breakpoints, however, showed differences in the patterns of deletion/insertions between p190 and p210. To explore the possibility that recombinase-activating gene (RAG) activity might be involved in ALL, we performed extra-chromosomal recombination assays for cases with breakpoints close to potential cryptic recombination signal sequence (cRSS) sites. Of 13 ALL cases tested, 1/10 with p190 and 1/3 with p210 precisely recapitulated the forward BCR-ABL breakpoint and 1/10 with p190 precisely recapitulated the reciprocal breakpoint. In contrast, neither of the p210 CMLs tested showed functional cRSSs. Thus, although the t(9;22) does not arise from aberrant variable (V), joining (J) and diversity (D) (V(D)J) recombination, our data suggest that in a subset of ALL cases RAG might create one of the initiating double-strand breaks.

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AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH Translocations

Cited by 412 publications

References 80 publications

Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

Role of the translocation partner in protection against AID-dependent chromosomal translocations

Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation

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