MicroRNA-155 Suppresses Activation-Induced Cytidine Deaminase-Mediated Myc-Igh Translocation

Dorsett, Yair; McBride, Kevin M.; Janković, Mila; Gazumyan, Anna; Thai, To Ha; Robbiani, Davide F.; Virgilio, Michela Di; Reina‐San‐Martin, Bernardo; Heidkamp, Gordon F.; Schwickert, Tanja A.; Eisenreich, Thomas; Rajewsky, Klaus; Nussenzweig, Michel C.

doi:10.1016/j.immuni.2008.04.002

Cited by 424 publications

(386 citation statements)

References 73 publications

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“…Indeed, it is possible that the diminished CSR obtained with some of the export-proficient mutant NESs might at least in part be the direct result of their diminished stability: the abundance of AID in normal B cells is known to be tightly controlled, with the efficiency of CSR being very sensitive to AID expression levels (15)(16)(17)(18)(19). Such a requirement for both export and abundance might nicely explain the CSR-deficiency exhibited by the AID P20 mutant (8), which carries a 34-aa insertion upstream of the NES, as we find that this mutant exhibits diminished stability although retaining a functional export sequence.…”

Section: Discussionmentioning

confidence: 99%

The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence

Geisberger

Rada²,

Neuberger³

2009

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

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The carboxyterminal region of activation-induced deaminase (AID) is required for its function in Ig class switch recombination (CSR) and also contains a nuclear-export sequence (NES). Here, based on an extensive fine-structure mutation analysis of the AID NES, as well as from AID chimeras bearing heterologous NESs, we show that while a functional NES is indeed essential for CSR, it is not sufficient. The precise nature of the NES is critical both for AID stabilization and CSR function: minor changes in the NES can perturb stabilization and CSR without jeopardizing nuclear export. The results indicate that the AID NES fulfills a function beyond simply providing a signal for nuclear export and suggest the possibility that the quality of exportin-binding may be critical to the stabilization of AID and its activity in CSR.activation-induced deaminase ͉ antibody diversification ͉ immunoglobulin class switching ͉ exportin ͉ nuclear transport A ctivation-induced deaminase (AID) plays a central role in antibody gene-diversification, triggering both somatic hypermutation (SHM) and class-switch recombination (CSR) by deaminating deoxycytidine residues within the Ig locus to yield deoxyuridine (1, 2).AID is largely found in the cytoplasm of activated B cells but shuttles between cytoplasm and nucleus (3-6). The C-terminal amino acids of AID comprise a nuclear-export sequence (NES): removal of this NES causes AID to be restricted to the nucleus, whereas its addition to a heterologous nuclear protein drives export of the fusion protein into the cytoplasm (3-5). The sequence of the AID C-terminus conforms well to the consensus established for substrates of the Crm1-dependent export machinery: in keeping with this, export mediated by the AID NES is sensitive to leptomycin B.Analysis of both clinical and contrived mutations in AID have revealed that the AID C-terminal region is also essential for its function in CSR, although not in SHM (7-9). The C-terminal mutations that interfere with AID's ability to potentiate CSR do not compromise its ability to deaminate deoxycytidine in biochemical or bacterial genetic assays. Thus, as previously suggested by others, either the nuclear/cytoplasmic shuttling of AID must be specifically required for CSR or, alternatively, factors specific for CSR must interact with the C-terminal region of AID in an area overlapping the NES (4, 5, 7-9).It was with a view to discriminating these possibilities that we embarked on a refined mutagenic dissection of the AID NES and investigated the ability of heterologous NESs to substitute for the AID NES. Our results suggest that although nuclear export is likely necessary for CSR, this is not the sole function of the AID C-terminal region, with the data raising the possibility that successful CSR depends on the precise quality of AID binding to exportin or a related protein. Results NES Function and CSR Correlate in Alanine-Scanning Mutagenesis.To ascertain whether there was a correlation between export activity and CSR, we performed an alanine-scanning mut...

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Section: Discussionmentioning

confidence: 99%

The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence

Geisberger

Rada²,

Neuberger³

2009

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

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“…41 It has also been demonstrated that the failure of miR-155-deficient B cells to generate highaffinity switched antibodies appears not because of a defect in somatic hypermutation or class-switch recombination, but more likely to a defect in the differentiation or survival of plasmablasts. 42 The predominance of infra-expressed miRNAs in myeloma samples is consistent with the global decrease in miRNA levels observed in other human cancers.…”

Section: Tablementioning

confidence: 99%

Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling

et al. 2010

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Specific microRNA (miRNA) signatures have been associated with different cytogenetic subtypes in acute leukemias. This finding prompted us to investigate potential associations between genetic abnormalities in multiple myeloma (MM) and singular miRNA expression profiles. Moreover, global gene expression profiling was also analyzed to find correlated miRNA gene expression and select miRNA target genes that show such correlation. For this purpose, we analyzed the expression level of 365 miRNAs and the gene expression profiling in 60 newly diagnosed MM patients, selected to represent the most relevant recurrent genetic abnormalities. Supervised analysis showed significantly deregulated miRNAs in the different cytogenetic subtypes as compared with normal PC. It is interesting to note that miR-1 and miR-133a clustered on the same chromosomal loci, were specifically overexpressed in the cases with t(14;16). The analysis of the relationship between miRNA expression and their respective target genes showed a conserved inverse correlation between several miRNAs deregulated in MM cells and CCND2 expression level. These results illustrate, for the first time, that miRNA expression pattern in MM is associated with genetic abnormalities, and that the correlation of the expression profile of miRNA and their putative mRNA targets is useful to find statistically significant protein-coding genes in MM pathogenesis associated with changes in specific miRNAs.

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“…This is highlighted by the cancer predisposition phenotype observed in transgenic mice overexpressing AID 7 , by the finding that ectopic SHM can occur in proto-oncogenes and tumor suppressor genes [8][9][10] and by the involvement of AID in oncogenic chromosomal translocations 11,12 . AID is normally induced in germinal center B cells 13 but in order to ensure that the genetic modifications it can cause are largely restricted to the Ig loci, there are multiple points of posttranscriptional regulation such as regulation of mRNA stability and translation [14][15][16] , subcellular localization 17,18 , protein stability 19 and modification by phosphorylation [20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Patenaude

Orthwein

et al. 2009

Nat Struct Mol Biol

134

175

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The enzyme Activation Induced Deaminase (AID) triggers antibody diversification in B-cells by catalyzing deamination and consequently mutation of immunoglobulin genes. To minimize off-target deamination, AID is restrained by several regulatory mechanisms including nuclear exclusion, thought to be mediated exclusively by active nuclear export. Here we identify two other mechanisms involved in controlling AID subcellular localization. AID is unable to passively diffuse into the nucleus, despite its small size, its nuclear entry requiring active import mediated by a conformational nuclear localization sequence (NLS). We also identify a determinant for AID cytoplasmic retention in its Cterminus, which hampers diffusion to the nucleus, competes with nuclear import and is critical for maintaining the predominantly cytoplasmic localization of AID in steady-state conditions. Blocking nuclear import alters the balance between these processes in favor of cytoplasmic retention, resulting in reduced isotype class switching.3

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MicroRNA-155 Suppresses Activation-Induced Cytidine Deaminase-Mediated Myc-Igh Translocation

Cited by 424 publications

References 73 publications

The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence

The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence

Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling

Active nuclear import and cytoplasmic retention of activation-induced deaminase

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