G-quadruplex DNA targeting alters class-switch recombination in B cells and attenuates allergic inflammation

Dalloul, Zeinab; Chenuet, Pauline; Dalloul, Iman; Boyer, François; Aldigier, Jean-Claude; Laffleur, Brice; Makhour, Yolla El; Ryffel, Bernhard; Quesniaux, Valérie; Togbé, Dieudonnée; Mergny, Jean‐Louis; Cook-Moreau, Jeanne; Cogné, Michel

doi:10.1016/j.jaci.2018.06.011

“…These investigations are still at their beginning stages, but show the importance of G4 formation for V(D)J recombination. During V(D)J recombination non-canonical DDR (ncDDR) is also activated [145], which is essential to drive gene activation needed for B-cell development. Whether or not these events depend on G4 structures has not been determined yet.…”

Section: Non-homologous End Joining (Nhej)mentioning

confidence: 99%

The Relevance of G-Quadruplexes for DNA Repair

Linke

¹

,

Limmer

²

,

Juranek

³

et al. 2021

IJMS

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DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

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“…In S regions, the non-template strand is G-rich, promoting R-loop formation and G4 DNA formation [18,19,25]. In S regions, G4-DNA promotes the occurrence of DNA nicks and further excision by exonuclease 1, while pharmacological agents binding G4-DNA can inhibit CSR [18,26,27]. I n vitro , G4-DNA was also shown to provide a type of structured DNA which favors the activity of Activation-Induced Deaminase (AID) [19].…”

Section: Discussionmentioning

confidence: 99%

Locus suicide recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues

Dalloul

¹

,

Boyer

²

,

Dalloul

³

et al. 2019

Self Cite

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B-cell activation yields abundant cell death in parallel to clonal amplification and remodeling of immunoglobulin (Ig) genes by activation-induced deaminase (AID). AID promotes affinity maturation of Ig variable regions and class switch recombination (CSR) in mature B lymphocytes. In the IgH locus, these processes are under control of the 3’ regulatory region (3’RR) super-enhancer, a region demonstrated in the mouse to be both transcribed and itself targeted by AID-mediated recombination. Alternatively to CSR, IgH deletions joining Sμ to “like-switch” DNA repeats that flank the 3’ super-enhancer can thus accomplish so-called “locus suicide recombination” (LSR) in mouse B-cells. Using an optimized LSR-seq high throughput method, we now show that AID-mediated LSR is evolutionarily conserved and also actively occurs in humans, providing an activation-induced cell death pathway in multiple conditions of B-cell activation. LSR either focuses on the functional IgH allele or is bi-allelic, and its signature is mainly detected when LSR is ongoing while it vanishes from fully differentiated plasma cells or from “resting” blood memory B-cells. Highly diversified breakpoints are distributed either within the upstream (3’RR1) or downstream (3’RR2) copies of the IgH 3’ super-enhancer and all conditions activating CSR in vitro also seem to trigger LSR although TLR ligation appeared the most efficient. Molecular analysis of breakpoints and junctions confirms that LSR is AID-dependent and reveals junctional sequences somehow similar to CSR junctions but with increased usage of microhomologies.

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“…where it promotes the initiation or extension of R-loops, and also often determines tandem G-repeats with potential to form G4 DNA [18,19,25]. In S regions, G4-DNA promotes the occurrence of DNA nicks and further excision by exonuclease 1, while pharmacological agents binding G4-DNA can inhibit CSR [18,26,27]. In vitro, G4-DNA was also shown to provide a type of structured DNA which favors the activity of Activation-Induced Deaminase (AID) [19].…”

Section: Discussionmentioning

confidence: 99%

Locus Suicide Recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues

Cogné

¹

,

Dalloul

²

,

Boyer

³

et al. 2018

Preprint

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B-cell activation yields abundant cell death in parallel to clonal amplification and remodeling of immunoglobulin (Ig) genes by activation-induced deaminase (AID). AID promotes affinity maturation of Ig variable regions and class switch recombination (CSR) in mature B lymphocytes. In the IgH locus, these processes are under control by the 3' regulatory region (3'RR) super-enhancer, a region demonstrated in the mouse to be both transcribed and itself targeted by AID-mediated recombination. Alternatively to CSR, IgH deletions joining Sµ to "like-switch" DNA repeats that flank the 3' super-enhancer can thus accomplish so-called "locus suicide recombination" (LSR) in mouse B-cells. We now show that AID-mediated LSR also actively occurs in humans, and provides an activationinduced cell death pathway in multiple conditions of B-cell activation. LSR deletions either focus on the functional IgH allele or are bi-allelic, since they can only be detected when they are ongoing and their signature vanishes from fully differentiated plasma cells or from "resting" blood memory B-cells, but readily reappears when such memory Bcells are re-stimulated in vitro. Highly diversified breakpoints are distributed either within the upstream (3'RR1) or downstream (3'RR2) copies of the IgH 3' super-enhancer and all conditions activating CSR in vitro also seem to trigger LSR. AUTHOR SUMMARYClass switch recombination, initiated by the activation-induced deaminase enzyme rearranges immunoglobulin (Ig) genes in order to replace expression of IgM by IgG, IgA or IgE. A variant form of this event, locus suicide recombination (LSR), was previously reported in mouse B-lymphocytes and simply deletes all functional Ig constant genes, thus terminating B-cell function. This study first demonstrates that the structure of the human Ig heavy chain locus provides an ideal target for LSR, and is thus actively (but transiently) affected by this deletional process at the activated B-cell stage. LSR then yields recombined genes that do not support B-cell survival and which thus become undetectable among long-lived memory B-cells or plasma cells. INTRODUCTIONHumoral immune responses and immunoglobulin (Ig) production rely on the selection of B-cells harboring antigen (Ag)-specific B-cell receptors (BCRs). This selection implies not only proliferation and differentiation of those cells optimally binding Ag but also elimination of the less efficient or inappropriately activated cells. The latter can be accomplished through various pathways leading to anergy, death-by-neglect or activation-induced cell death (AICD).While AICD pathways have been characterized in detail for T-cells, and notably involve FAS-induced apoptosis, they are less documented in B-cells. A major and unique feature of mature B-cells during Ag-driven responses, is their ability to reshape their genome, and more specifically Ig genes, after activation-induced deaminase (AID)-dependent modifications. Somatic hypermutation (SHM) within germinal centers (GC) can yield cells with higher affinity V d...

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G-quadruplex DNA targeting alters class-switch recombination in B cells and attenuates allergic inflammation

Abstract: , and ERDF. Z.D. was supported by a fellowship from Fondation Française pour la Recherche contre le My elome et les Gammapathies monoclonales (F.F.R.M.G.). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

Cited by 19 publications

References 9 publications

The Relevance of G-Quadruplexes for DNA Repair

The Relevance of G-Quadruplexes for DNA Repair

Locus suicide recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues

Locus Suicide Recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues

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