Efficient AID targeting of switch regions is not sufficient for optimal class switch recombination

Bonaud, Amélie; Lechouane, Fabien; Noir, Sandrine Le; Monestier, Olivier; Cogné, Michel; Sirac, Christophe

doi:10.1038/ncomms8613

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…We amplified immunoglobulin variable loci by PCR from purified naive B cells (culture day 0), GCBs sorted from ex vivo cultures for 6 days, and naive B cells and GCBs sorted from immunized mice. Analysis of sequencing data revealed a significant increase in indels and missense mutations in organoid GC B cells as compared with naive B cells, similar to in vivo GC B cells 15 (Fig. 3n, o).…”

Section: Resultssupporting

confidence: 59%

EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop

et al. 2017

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The EZH2 histone methyltransferase is required for B cells to form germinal centers (GC). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21Cip1). Deletion of Cdkn1a rescues the GC reaction in Ezh2 −/− mice. Using a 3D B cell follicular organoid system that mimics the GC reaction, we show that depletion of EZH2 suppresses G1 to S phase transition of GC B cells in a Cdkn1a-dependent manner. GC B cells of Cdkn1a −/− Ezh2 −/− mice have high levels of phospho-Rb, indicating that loss of Cdkn1a enables progression of cell cycle. Moreover, the transcription factor E2F1 induces EZH2 during the GC reaction. E2f1 −/− mice manifest impaired GC responses, which is rescued by restoring EZH2 expression, thus defining a positive feedback loop in which EZH2 controls GC B cell proliferation by suppressing CDKN1A, enabling cell cycle progression with a concomitant phosphorylation of Rb and release of E2F1.

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Section: Resultssupporting

confidence: 59%

EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop

et al. 2017

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“…Regulatory elements are also important to control and complete CSR. Insertion of a cassette including S regions at the IgL locus (an AID physiological target), strongly induces AID targeting (mutations and internal deletions to these S regions) but very few long distance CSR-like events are observed between them, probably because of the absence of the 3′RR on the IgL containing chromosome 73 , suggesting additional levels of regulation to create an efficient synapsis for CSR.…”

Section: Long-range Interactions and Dna Element Synapsis For Optimalmentioning

confidence: 99%

RNA Exosome and Non-coding RNA-Coupled Mechanisms in AID-Mediated Genomic Alterations

Laffleur

Basu

Lim

2017

Journal of Molecular Biology

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The eukaryotic RNA exosome is a well-conserved protein complex with ribonuclease activity implicated in RNA metabolism. Various families of non-coding RNAs (ncRNAs) have been identified as substrates of the complex, underscoring its role as a ncRNA processing/degradation unit. However, the role of RNA exosome and its RNA processing activity on DNA mutagenesis/alteration events have not been investigated until recently. B lymphocytes use two DNA alteration mechanisms, class switch recombination (CSR) and somatic hypermutation (SHM), to re-engineer their antibody gene expressing loci until a tailored antibody gene for a specific antigen is satisfactorily generated. CSR and SHM require the essential activity of the DNA activation induced cytidine deaminase (AID). Causing collateral damage to the B cell genome during CSR and SHM, AID induces unwanted (and sometimes oncogenic) mutations at numerous non-immunoglobulin gene sequences. Recent studies have revealed that AID’s DNA mutator activity is regulated by the RNA exosome complex, thus providing an example of a mechanism that relates DNA mutagenesis with RNA processing. Here, we review the emergent functions of RNA exosome during CSR, SHM and other chromosomal alterations in B cells, and discuss implications relevant to mechanisms that maintain B cell genomic integrity.

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“…Although AID localization to and deamination of S-region DNA is required for CSR, additional factors downstream of germline transcription and AID recruitment are necessary for wild-type levels of CSR 3 , 45 , 61 , 62 . The conversion of deaminated DNA into DSBs requires many proteins from DNA repair pathways that have evolved to respond to general DNA damage.…”

Section: Multiple Dna Repair Pathways In Csrmentioning

confidence: 99%

Generating and repairing genetically programmed DNA breaks during immunoglobulin class switch recombination

et al. 2018

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Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR. Within the Ig locus, DNA repair pathways are diverted from their canonical role in maintaining genomic integrity to permit AID-directed mutation and deletion of gene coding segments. Recently identified proteins, genes, and regulatory networks have provided new insights into the temporally and spatially coordinated molecular interactions that control the formation and repair of DSBs within the Ig locus. Unravelling the genetic program that allows B cells to selectively alter the Ig coding regions while protecting non-Ig genes from DNA damage advances our understanding of the molecular processes that maintain genomic integrity as well as humoral immunity.

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Efficient AID targeting of switch regions is not sufficient for optimal class switch recombination

Cited by 10 publications

References 44 publications

EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop

EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop

RNA Exosome and Non-coding RNA-Coupled Mechanisms in AID-Mediated Genomic Alterations

Generating and repairing genetically programmed DNA breaks during immunoglobulin class switch recombination

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