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

Abstract

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...

Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70

“…Indeed, C-NHEJ has been shown to join DSBs on the same chromosome preferentially and thereby to suppress translocations (39). Moreover, the DSB response involving factors such as ATM, 53BP1, and H2AX has been shown to be required for normal joining of DSBs via NHEJ (25,36,40). In this regard, the DSB response also has been suggested as promoting long-range joining of intrachromosomal DSBs (41).…”

Epidemiology: clues to the pathogenesis of Burkitt lymphoma

“…These translocations are normally prevented by the tumour suppressor genes ATM, CDKN2A (p19, ARF) and TP53, consistent with the ability of these genes to inhibit progression through the cell cycle and to initiate DNA repair or apoptosis in the presence of DNA damage (although it appears that different molecules may protect against different translocations, (Jankovic et al, 2010), such that these same tumour suppressor genes would not necessarily prevent a translocation involving a different partner with IGH (Ramiro et al, 2007). The persistence of translocations is, conversely, inhibited by the pro-apoptotic genes BBC3 (PUMA), BCL2L11 (BIM) and RIPK4 (PKCdelta) and enhanced by the anti-apoptotic BCL2L1 (BCL-XL) and TNFSF13B (BAFF), while FAS-induced apoptosis is involved in the elimination of cells in which a functional class switch is not created.…”

Role of activation‐induced cytidine deaminase in the progression of follicular lymphoma

“…In addition, expression of AID was shown to lead to the generation of point mutations for SHM and CSR, resulting in DNA damage and apoptosis, (37) probably in the deregulated expression of anti-apoptotic factors such as bcl-2 and bcl-XL. (38) These findings suggest that cell-cycle arrest or apoptosis can be ultimately induced when sufficient AID is subsequently expressed in B lymphocytes after CSR. Interestingly, among our sources of lymphoma samples, two BLs and one de novo Burkitt-like DLBCL (BCLU1) did express c-myc and AID, but not bcl-2, and they did not undergo G 0 ⁄ G 1 arrest (data not shown).…”