Influence of switch region length on immunoglobulin class switch recombination

Zarrin, Ali A.; Tian, Ming; Wang, Jing H.; Borjeson, Tiffany M.; Alt, Frederick W.

doi:10.1073/pnas.0409847102

Cited by 52 publications

(45 citation statements)

References 30 publications

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“…The 59 probe was a 1.5-kb XbaI-XbaI fragment upstream of the first exon of Bcl6, and the 39 probe was a 1.4-kb BamHI-HindIII fragment from the first intron of Bcl6. The configuration of the targeted allele was further confirmed by additional Southern blots with probes that hybridized to the Sg1 region (35). For the deletion of neo r cassette through two flanking loxP sites, targeted ES clones were infected with recombinant adenovirus that expressed Cre recombinase.…”

Section: Embryonic Stem Cells Targeting and Generation Of Bcl6mentioning

confidence: 99%

“…A 3.5-kb NotI-SalI fragment containing Bcl6 genomic DNA was used as the 39 homology arm. The targeting construct for the Bcl6 locus was generated by insertion of a 4-kb endogenous Sg1 region as a NotI-SalI fragment (35) upstream of the 39 homology arm. The targeting construct was transfected into TC1 embryonic stem (ES) cells.…”

Section: Embryonic Stem Cells Targeting and Generation Of Bcl6mentioning

confidence: 99%

“…This strategy excluded the influence of Igh cis regulatory elements, thereby allowing a direct test of the role of DNA sequences in regulating AID activity. The core Sg1 region (4 kb) was chosen because it supports CSR efficiently in vivo in its endogenous Igh locus (35). We generated Bcl6…”

mentioning

confidence: 99%

“…To determine whether S region sequences per se, independent of Igh cis regulatory elements, can regulate AID targeting efficiency, we inserted a core Sg1 region (35) into the first intron of the mouse Bcl6 gene via a gene-targeting approach. This strategy excluded the influence of Igh cis regulatory elements, thereby allowing a direct test of the role of DNA sequences in regulating AID activity.…”

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confidence: 99%

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Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Chen

Viboolsittiseri

O’Connor

et al. 2012

The Journal of Immunology

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Activation-induced deaminase (AID) catalyses class switch recombination (CSR) and somatic hypermutation (SHM) in B lymphocytes to enhance Ab diversity. CSR involves breaking and rejoining highly repetitive switch (S) regions in the IgH (Igh) locus. S regions appear to be preferential targets of AID. To determine whether S region sequence per se, independent of Igh cis regulatory elements, can influence AID targeting efficiency and mutation frequency, we established a knock-in mouse model by inserting a core Sγ1 region into the first intron of proto-oncogene Bcl6, which is a non-Ig target of SHM. We found that the mutation frequency of the inserted Sγ1 region was dramatically higher than that of the adjacent Bcl6 endogenous sequence. Mechanistically, S region-enhanced SHM was associated with increased recruitment of AID and RNA polymerase II, together with Spt5, albeit to a lesser extent. Our studies demonstrate that target DNA sequences influence mutation frequency via regulating AID recruitment. We propose that the nucleotide sequence preference may serve as an additional layer of AID regulation by restricting its mutagenic activity to specific sequences despite the observation that AID has the potential to access the genome widely.

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Section: Embryonic Stem Cells Targeting and Generation Of Bcl6mentioning

confidence: 99%

Section: Embryonic Stem Cells Targeting and Generation Of Bcl6mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Chen

Viboolsittiseri

O’Connor

et al. 2012

The Journal of Immunology

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“…The numbers of tandem repetitive sequences within S regions determine how efficiently a particular S region can recruit AID to carry out CSR (33). In addition, mammalian S regions are G rich on the coding strand, a feature that is considered important for formation of R-loops and DNA/RNA hybrid strands, making them even better AID hot spots (30,34).…”

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confidence: 99%

Increased Targeting of Donor Switch Region and IgE in Sγ1-Deficient B Cells

Misaghi¹,

Garris²,

Sun³

et al. 2010

The Journal of Immunology

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Ab class switch recombination involves a recombination between two repetitive DNA sequences known as switch (S) regions that vary in length, content, and density of the repeats. Abs expressed by B cells are diversified by somatic hypermutation and class switch recombination. Both class switch recombination and somatic hypermutation are initiated by activation-induced cytidine deaminase (AID), which preferentially recognizes certain hot spots that are far more enriched in the S regions. We found that removal of the largest S region, Sγ1 (10 kb), in mice can result in the accumulation of mutations and short-range intra-S recombination in the donor Sμ region. Furthermore, elevated levels of IgE were detected in trinitrophenol-OVA–immunized mice and in anti-CD40 plus IL-4–stimulated B cells in vitro. We propose that AID availability and targeting in part might be regulated by its DNA substrate. Thus, prominently transcribed S regions, such as Sγ1, might provide a sufficient sink for AID protein to titrate away AID from other accessible sites within or outside the Ig locus.

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B‐Cell Antigen Receptor: Assembly and Diversification

Mohammad¹,

Guillou²,

Ghamlouch³

et al. 2020

Encyclopedia of Life Sciences

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Immunoglobulin (Ig) genes of mammalian B cells undergo two processes that diversify their genomic sequence and structure. The first one concerns the BCR assembly that is achieved through a combinatorial rearrangement of a large number of V, D and J gene segments. This process is essential for B‐cell development and occurs during early B‐cell differentiation in the bone marrow without antigenic challenge. The second process includes somatic hypermutation (SHM), and class switch recombination (CSR), start when the B cell encounters an antigen at the periphery. While the two processes share the action of ubiquitous DNA repair factors to carry out all the steps necessary for creating recombination and mutations in genomic DNA, they are initiated by different lymphoid‐specific factors. On one hand, the action of recombination activating genes 1 and 2 (RAG1 and RAG2) is required for the V(D) J rearrangements and, on the other hand, the action of activation‐induced cytidine deaminase (AID) for both SHM and CSR. The ultimate goal of these diversification mechanisms is to create a dynamic and robust immune response. Key Concepts V(D)J recombination is a programmed that generates B‐ and T‐cell receptors in vertebrates (BCR and TCR). V(D)J recombination requires precise cutting of the DNA at recombination signal sequences (RSS) followed by rejoining of the resulting termini. Imprecisions during the ends‐joining reaction contribute significantly to increasing the variability of the resulting functional BCR and TCR. RAG1, RAG2 and TdT are the three lymphoid‐specific factors needed for V(D)J recombination and for the junctional diversity observed during lymphoid development. B‐cells provide the antibody‐mediated immune response (humoral immunity). It can generate antibodies to an immense variety of pathogenic antigens. Somatic hypermutation (SHM) and class switch recombination (CSR) occur only in germinal centre B cells. During SHM, DNA repair mechanisms are diverted from their canonical role in preserving genomic integrity to permit high rate of mutations. SHM and CSR both occur in germinal centre in secondary lymphoid tissues and require activation‐induced cytidine deaminase (AID). AID deaminates deoxy‐cytosine on single‐stranded DNA. Ten–eleven translocation (TET) proteins (mainly TET2et TET3) are key regulators of immunoglobulin light chain rearrangement, class switch recombination and plasma cell differentiation.

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Influence of switch region length on immunoglobulin class switch recombination

Cited by 52 publications

References 30 publications

Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Increased Targeting of Donor Switch Region and IgE in Sγ1-Deficient B Cells

B‐Cell Antigen Receptor: Assembly and Diversification

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