Repression of human activation induced cytidine deaminase by miR-93 and miR-155

Borchert, Glen M.; Holton, Nathaniel W; Larson, Erik D.

doi:10.1186/1471-2407-11-347

Cited by 43 publications

(20 citation statements)

References 50 publications

(56 reference statements)

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“…Several miRNAs, including miR-155, miR-181b, and miR-361, have been implicated in regulating the vigor of AID mRNA by binding to its 3′-untranslated region (3′-UTR) (Borchert, Holton, & Larson, et al, 2011; de Yebenes et al, 2008; Dorsett et al, 2008; Teng et al, 2008). In addition to playing a role in general GC structure and function, miR-155 was found to be upregulated in murine B cells undergoing CSR (Teng et al, 2008; Thai et al, 2007).…”

Section: Multifaceted Regulation Of Aid Expression and Activitymentioning

confidence: 99%

Regulation of Immunoglobulin Class-Switch Recombination

Matthews

Zheng

DiMenna

et al. 2014

Advances in Immunology

118

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Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cμ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as “Ch genes”, e.g., Cγ, Cε, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sμ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming.

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Section: Multifaceted Regulation Of Aid Expression and Activitymentioning

confidence: 99%

Regulation of Immunoglobulin Class-Switch Recombination

Matthews

Zheng

DiMenna

et al. 2014

Advances in Immunology

118

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“…In the same manner, AID misexpression in human colonic cells resulted in the accumulation of TP53 mutations (157). In addition, misexpression of AID at various levels was detected in about one third of primary lung cancers and lung cancer cell lines (158) and in numerous breast cancer cell lines (68, 159). In the human MCF-7 breast cancer cell line, AID expression is negatively regulated by miR-155 and miR-93 (68).…”

Section: Dysregulated Aid Expression and Tumorigenesismentioning

confidence: 99%

“…In addition, misexpression of AID at various levels was detected in about one third of primary lung cancers and lung cancer cell lines (158) and in numerous breast cancer cell lines (68, 159). In the human MCF-7 breast cancer cell line, AID expression is negatively regulated by miR-155 and miR-93 (68). AID expression is also associated with TP53 mutations in lung cancer cells (158).…”

Section: Dysregulated Aid Expression and Tumorigenesismentioning

confidence: 99%

Regulation ofAicdaexpression and AID activity

2013

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Activation-induced cytidine deaminase (AID) is expressed in a B cell differentiation stage-specific fashion and is essential for immunoglobulin (Ig) gene class switch DNA recombination (CSR) and somatic hypermutation (SHM). CSR and SHM play a central role in the maturation of antibody and autoantibody responses. AID displays a mutagenic activity by catalyzing targeted deamination of deoxycytidine (dC) residues in DNA resulting in dU:dG mismatches, which are processed into point-mutations in SHM or double-strand breaks (DSBs) in CSR. Although AID specifically targets the Ig gene loci (IgH, Igκ and Igλ), it can also home into a wide array of non-Ig genes in B- and non-B-cell backgrounds. Aberrant expression of AID is associated with multiple diseases such as allergy, inflammation, autoimmunity and cancer. In autoimmune systemic lupus erythematosus, dysregulated AID expression underpins increased CSR, SHM and autoantibody production. As a potent mutator, AID is under stringent transcriptional, post-transcriptional and post-translational regulation. AID is also regulated in its targeting and enzymatic function. In resting naïve or memory B cells, AID transcripts and protein are undetectable. These, however, are readily and significantly upregulated in B cells induced to undergo CSR and/or SHM. Transcription factors, such as HoxC4 and NF-κB, which are upregulated in a B cell lineage- and/or differentiation stage-specific manner, regulate the induction of AID. HoxC4 induces AID expression by directly binding to the AID gene promoter through an evolutionarily conserved 5’-ATTT-3’ motif. HoxC4 is induced by the same stimuli that induce AID and CSR. It is further upregulated by estrogen through three estrogen responsive elements in its promoter region. The targeting of AID to switch (S) regions is mediated by 14-3-3 adaptor proteins, which specifically bind to 5′-AGCT-3′ repeats that are exist at high frequency in S region cores. Like HoxC4, 14-3-3 adaptors are induced by the same stimuli that induce AID. These include “primary” inducing stimuli, that is, those that play a major role in inducing AID, i.e., engagement of CD40 by CD154, engagement of Toll-like receptors (TLRs) by microbial-associated molecular patterns (MAMPs) and cross-linking of the BCR, as synergized by “secondary” inducing stimuli, that is, those that synergize for AID induction and specify CSR to different isotypes, i.e., switch-directing cytokines IL-4, TGF-β or IFN-γ. In this review, we focus on the multi-levels regulation of AID expression and activity. We also discuss the dysregulation or misexpression of AID in autoimmunity and tumorigenesis.

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“…AID is also downregulated by other miRNAs, including miR-181b and miR-93 (human B cells only), that target different sites in the 3′ UTR of Aicda transcripts (31, 76, 78). miR-181b expression is downregulated upon B-cell activation.…”

Section: Mirna In Immune Responsesmentioning

confidence: 99%

MicroRNAs in lupus

2014

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of an array of pathogenic autoantibodies, including high-affinity anti-dsDNA IgG antibodies, which plays an important role in disease development and progression. Lupus preferentially affects women during their reproductive years. The pathogenesis of lupus is contributed by both genetic factors and epigenetic modifications that arise from exposure to the environment. Epigenetic marks, including DNA methylation, histone post-translational modifications and microRNAs (miRNAs), interact with genetic programs to regulate immune responses. Epigenetic modifications influence gene expression and modulate B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses to exogenous antigens or self-antigens, such as chromatin, histones and dsDNA in lupus. miRNAs play key roles in the post-transcriptional regulation of most gene-regulatory pathways and regulate both the innate and the adaptive immune responses. In mice, dysregulation of miRNAs leads to aberrant immune responses and development of systemic autoimmunity. Altered miRNA expression has been reported in human autoimmune diseases, including lupus. The dysregulation of miRNAs in lupus could be the result of multiple environmental factors, such as sex hormones and viral or bacterial infection. Modulation of miRNA is a potential therapeutic strategy for lupus.

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Repression of human activation induced cytidine deaminase by miR-93 and miR-155

Cited by 43 publications

References 50 publications

Regulation of Immunoglobulin Class-Switch Recombination

Regulation of Immunoglobulin Class-Switch Recombination

Regulation ofAicdaexpression and AID activity

MicroRNAs in lupus

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